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.).

Prehospital stroke diagnostics using three different simulation methods: A pragmatic pilot study.

INTRODUCTION: The optimal pathway for ultra-early diagnostics and treatment in patients with acute stroke remains uncertain. The aim of this study was to investigate how three different methods of simulated, rural prehospital computed tomography (CT) affected the time to prehospital treatment decision in acute stroke. MATERIALS AND METHODS: In this pragmatic, simulation, pilot study of prehospital CT we investigated a conventional ambulance with transport to a standard care rural stationary CT machine managed by paramedics, a Mobile Stroke Unit (MSU), and a helicopter with a simulated CT machine. Each modality completed 20 real-life dispatches combined with simulation of predetermined animated patient cases with acute stroke symptoms and CT images. The primary endpoint of the study was the time from alarm to treatment decision. RESULTS: Median time from alarm to the treatment decision differed significantly between the three groups (p = 0.0005), with 38 min for rural CT, 33 min for the MSU, and 30 min for the helicopter. There was no difference in time when comparing rural CT with MSU, nor when comparing the MSU with the helicopter. There was a difference in time to treatment decision between the rural CT and the helicopter (p < 0.0001). The helicopter had significantly lower estimated time from treatment decision to hospital (p = 0.001). DISSCUSSION/CONCLUSION: Prehospital CT can be organized in several ways depending on geography, resources and need. Further research on paramedic run rural CT, MSU in rural areas, and helicopter CT is needed to find the optimal strategy.

Haemorrhagic stroke and brain vascular malformations in women: risk factors and clinical features.

Haemorrhagic stroke is a severe condition with poor prognosis. Biological sex influences the risk factors, presentations, treatment, and patient outcomes of intracerebral haemorrhage, aneurysmal subarachnoid haemorrhage, and vascular malformations. Women are usually older at onset of intracerebral haemorrhage compared with men but have an increased risk of aneurysmal subarachnoid haemorrhage as they age. Female-specific factors such as pregnancy, eclampsia or pre-eclampsia, postmenopausal status, and hormone therapy influence a woman's long-term risk of haemorrhagic stroke. The presence of intracranial aneurysms, arteriovenous malformations, or cavernous malformations poses unique clinical dilemmas during pregnancy and delivery. In the absence of evidence-based guidelines for managing the low yet uncertain risk of haemorrhagic stroke during pregnancy and delivery in women with vascular malformations, multidisciplinary teams should carefully assess the risks and benefits of delivery methods for these patients. Health-care providers should recognise and address the challenges that women might have to confront when recovering from haemorrhagic stroke.

Telephone triage and dispatch of ambulances to patients with suspected and verified acute stroke - a descriptive study.

OBJECTIVES: In this study we aimed to explore EMCC triage of suspected and confirmed stroke patients to gain more knowledge about the initial phase of the acute stroke response chain. Accurate dispatch at the Emergency Medical Communication Center (EMCC) is crucial for optimal resource utilization in the prehospital service, and early identification of acute stroke is known to improve patient outcome. MATERIALS AND METHODS: We conducted a descriptive retrospective study based on data from the Emergency Department and EMCC records at a comprehensive stroke center in Oslo, Norway, during a six-month period (2019-2020). Patients dispatched with EMCC stroke criteria and/or discharged with a stroke diagnosis were included. We identified EMCC true positive, false positive and false negative stroke patients and estimated EMCC stroke sensitivity and positive predictive value (PPV). Furthermore, we analyzed prehospital time intervals and identified patient destinations to gain knowledge on ambulance services assessments. RESULTS: We included 1298 patients. EMCC stroke sensitivity was 77% (95% CI: 72 - 82%), and PPV was 16% (95% CI: 14 - 18%). EMCC false negative stroke patients experienced an increased median prehospital delay of 11 min (p < 0.001). Upon arrival at the scene, 68% of the EMCC false negative patients were identified as suspected stroke cases by the ambulance services. Similarly, 68% of the false positive stroke patients were either referred to a GP, out-of-hours GP acute clinic, local hospitals or left at the scene by the ambulance services, indicating that no obvious stroke symptoms were identified by ambulance personnel upon arrival at the scene. CONCLUSIONS: This study reveals a high EMCC stroke sensitivity and an extensive number of false positive stroke dispatches. By comparing the assessments made by both the EMCC and the ambulance service, we have identified specific patient groups that should be the focus for future research efforts aimed at improving the sensitivity and specificity of stroke recognition in the EMCC.

Noninvasive Assessment of Intracranial Pressure: Deformability Index as an Adjunct to Optic Nerve Sheath Diameter to Increase Diagnostic Ability.

BACKGROUND: Today, invasive intracranial pressure (ICP) measurement remains the standard, but its invasiveness limits availability. Here, we evaluate a novel ultrasound-based optic nerve sheath parameter called the deformability index (DI) and its ability to assess ICP noninvasively. Furthermore, we ask whether combining DI with optic nerve sheath diameter (ONSD), a more established parameter, results in increased diagnostic ability, as compared to using ONSD alone. METHODS: We prospectively included adult patients with traumatic brain injury with invasive ICP monitoring, which served as the reference measurement. Ultrasound images and videos of the optic nerve sheath were acquired. ONSD was measured at the bedside, whereas DI was calculated by semiautomated postprocessing of ultrasound videos. Correlations of ONSD and DI to ICP were explored, and a linear regression model combining ONSD and DI was compared to a linear regression model using ONSD alone. Ability of the noninvasive parameters to distinguish dichotomized ICP was evaluated using receiver operating characteristic curves, and a logistic regression model combining ONSD and DI was compared to a logistic regression model using ONSD alone. RESULTS: Forty-four ultrasound examinations were performed in 26 patients. Both DI (R = - 0.28; 95% confidence interval [CI] R < - 0.03; p = 0.03) and ONSD (R = 0.45; 95% CI R > 0.23; p < 0.01) correlated with ICP. When including both parameters in a combined model, the estimated correlation coefficient increased (R = 0.51; 95% CI R > 0.30; p < 0.01), compared to using ONSD alone, but the model improvement did not reach statistical significance (p = 0.09). Both DI (area under the curve [AUC] 0.69, 95% CI 0.53-0.83) and ONSD (AUC 0.72, 95% CI 0.56-0.86) displayed ability to distinguish ICP dichotomized at ICP ≥ 15 mm Hg. When using both parameters in a combined model, AUC increased (0.80, 95% CI 0.63-0.90), and the model improvement was statistically significant (p = 0.02). CONCLUSIONS: Combining ONSD with DI holds the potential of increasing the ability of optic nerve sheath parameters in the noninvasive assessment of ICP, compared to using ONSD alone, and further study of DI is warranted.

Experiences from a cluster-randomized trial (ParaNASPP) exploring triage and diagnostic accuracy in paramedic-suspected stroke: a qualitative interview study.

BACKGROUND AND PURPOSE: Timely prehospital stroke recognition was explored in the Paramedic Norwegian Acute Stroke Prehospital Project (ParaNASPP) by implementation of stroke education for paramedics and use of the National Institutes of Health Stroke Scale (NIHSS) through a mobile application. The study tested triage and facilitated communication between paramedics and stroke physicians. To complement the quantitative results of the clinical trial, a qualitative approach was used to identify factors that influence triage decisions and diagnostic accuracy in prehospital stroke recognition experienced by paramedics and stroke physicians. METHOD: Semi-structured qualitative individual interviews were performed following an interview guide. Informants were recruited from the enrolled paramedics and stroke physicians who participated in the ParaNASPP trial from Oslo University Hospital. Interviews were audio recorded, transcribed verbatim and approached inductively using the principles of thematic analysis. RESULTS: Fourteen interviews were conducted, with seven paramedics and seven stroke physicians. Across both groups two overarching themes were identified related to triage decisions and diagnostic accuracy in prehospital stroke recognition: prehospital NIHSS reliably improves clinical assessment and communication quality; overtriage is widely accepted whilst undertriage is not. CONCLUSION: Paramedics and stroke physicians described how prehospital NIHSS improved communication quality and reliably improved prehospital clinical assessment. The qualitative results support a rationale of an application algorithm to decide which NIHSS items should prompt immediate prenotification rather than a complete NIHSS as default.

Influence of Time to Achieve Target Systolic Blood Pressure on Outcome After Intracerebral Hemorrhage: The Blood Pressure in Acute Stroke Collaboration.

OBJECTIVE: To investigate whether an earlier time to achieving and maintaining systolic blood pressure (SBP) at 120 to 140 mm Hg is associated with favorable outcomes in a cohort of patients with acute intracerebral hemorrhage. METHODS: We pooled individual patient data from randomized controlled trials registered in the Blood Pressure in Acute Stroke Collaboration. Time was defined as time form symptom onset plus the time (hour) to first achieve and subsequently maintain SBP at 120 to 140 mm Hg over 24 hours. The primary outcome was functional status measured by the modified Rankin Scale at 90 to 180 days. A generalized linear mixed models was used, with adjustment for covariables and trial as a random effect. RESULTS: A total of 5761 patients (mean age, 64.0 [SD, 13.0], 2120 [36.8%] females) were included in analyses. Earlier SBP control was associated with better functional outcomes (modified Rankin Scale score, 3-6; odds ratio, 0.98 [95% CI, 0.97-0.99]) and a significant lower risk of hematoma expansion (0.98, 0.96-1.00). This association was stronger in patients with bigger baseline hematoma volume (>10 mL) compared with those with baseline hematoma volume ≤10 mL (0.006 for interaction). Earlier SBP control was not associated with cardiac or renal adverse events. CONCLUSIONS: Our study confirms a clear time relation between early versus later SBP control (120-140 mm Hg) and outcomes in the one-third of patients with intracerebral hemorrhage who attained sustained SBP levels within this range. These data provide further support for the value of early recognition, rapid transport, and prompt initiation of treatment of patients with intracerebral hemorrhage.

Sex and gender publications in brain health: a mapping review of the Asia-Pacific region.

INTRODUCTION: Reporting of sex and gender analysis in medical research has been shown to improve quality of the science and ensures findings are applicable to women and men. There is conflicting evidence on whether efforts by funding agencies and medical journals to encourage reporting of sex and gender analysis has resulted in tangible improvements. This study mapped the inclusion of sex and gender analysis in stroke and dementia research conducted in the Asia-Pacific region. METHODS: A systematic search for Asia-Pacific stroke and dementia research was conducted in PubMed and papers included from the period 2012 to 2022. Eligible studies were reviewed for inclusion of a primary sex or gender focus and categorized by type of sex and gender analysis. Author gender was determined using an algorithm and its associations with inclusion of sex and gender analysis examined. RESULTS: Total Asia-Pacific publications increased from 109 in 2012 to 313 in 2022, but the rate of studies with a primary sex or gender focus did not increase significantly (R2 = 0.06, F(1,9) = 0.59, p = 0.46). Australia, China, India, Japan and South Korea produced the most publications over the study period and were the only countries with at least 50 publications. The impact of author gender was mixed, with female first authorship associated with inclusion of sex or gender analysis and last female authorship associated with studies having a primary sex or gender focus. CONCLUSIONS: In the Asia-Pacific, brain health research is currently centered around high income countries and efforts are needed to ensure research findings are applicable through out the region. While there was a general increase in brain health publications over the last decade, the rate of sex and gender analysis was unchanged. This demonstrates that even with efforts in some countries in place, there is currently a lack of progress in the Asia-Pacific region to produce more research focusing on sex and gender analysis.

Blood Pressure Trajectories and Outcomes After Endovascular Thrombectomy for Acute Ischemic Stroke.

BACKGROUND: Data on systolic blood pressure (SBP) trajectories in the first 24 hours after endovascular thrombectomy (EVT) in acute ischemic stroke are limited. We sought to identify these trajectories and their relationship to outcomes. METHODS: We combined individual-level data from 5 studies of patients with acute ischemic stroke who underwent EVT and had individual blood pressure values after the end of the procedure. We used group-based trajectory analysis to identify the number and shape of SBP trajectories post-EVT. We used mixed effects regression models to identify associations between trajectory groups and outcomes adjusting for potential confounders and reported the respective adjusted odds ratios (aORs) and common odds ratios. RESULTS: There were 2640 total patients with acute ischemic stroke included in the analysis. The most parsimonious model identified 4 distinct SBP trajectories, that is, general directional patterns after repeated SBP measurements: high, moderate-high, moderate, and low. Patients in the higher blood pressure trajectory groups were older, had a higher prevalence of vascular risk factors, presented with more severe stroke syndromes, and were less likely to achieve successful recanalization after the EVT. In the adjusted analyses, only patients in the high-SBP trajectory were found to have significantly higher odds of early neurological deterioration (aOR, 1.84 [95% CI, 1.20-2.82]), intracranial hemorrhage (aOR, 1.84 [95% CI, 1.31-2.59]), mortality (aOR, 1.75 [95% CI, 1.21-2.53), death or disability (aOR, 1.63 [95% CI, 1.15-2.31]), and worse functional outcomes (adjusted common odds ratio,1.92 [95% CI, 1.47-2.50]). CONCLUSIONS: Patients follow distinct SBP trajectories in the first 24 hours after an EVT. Persistently elevated SBP after the procedure is associated with unfavorable short-term and long-term outcomes.

Association between blood pressure variability and outcomes after endovascular thrombectomy for acute ischemic stroke: An individual patient data meta-analysis.

INTRODUCTION: Data on the association between blood pressure variability (BPV) after endovascular thrombectomy (EVT) for acute ischemic stroke (AIS) and outcomes are limited. We sought to identify whether BPV within the first 24 hours post EVT was associated with key stroke outcomes. METHODS: We combined individual patient-data from five studies among AIS-patients who underwent EVT, that provided individual BP measurements after the end of the procedure. BPV was estimated as either systolic-BP (SBP) standard deviation (SD) or coefficient of variation (CV) over 24 h post-EVT. We used a logistic mixed-effects model to estimate the association [expressed as adjusted odds ratios (aOR)] between tertiles of BPV and outcomes of 90-day mortality, 90-day death or disability [modified Rankin Scale-score (mRS) > 2], 90-day functional impairment (⩾1-point increase across all mRS-scores), and symptomatic intracranial hemorrhage (sICH), adjusting for age, sex, stroke severity, co-morbidities, pretreatment with intravenous thrombolysis, successful recanalization, and mean SBP and diastolic-BP levels within the first 24 hours post EVT. RESULTS: There were 2640 AIS-patients included in the analysis. The highest tertile of SBP-SD was associated with higher 90-day mortality (aOR:1.44;95% CI:1.08-1.92), 90-day death or disability (aOR:1.49;95% CI:1.18-1.89), and 90-day functional impairment (adjusted common OR:1.42;95% CI:1.18-1.72), but not with sICH (aOR:1.22;95% CI:0.76-1.98). Similarly, the highest tertile of SBP-CV was associated with higher 90-day mortality (aOR:1.33;95% CI:1.01-1.74), 90-day death or disability (aOR:1.50;95% CI:1.19-1.89), and 90-day functional impairment (adjusted common OR:1.38;95% CI:1.15-1.65), but not with sICH (aOR:1.33;95% CI:0.83-2.14). CONCLUSIONS: BPV after EVT appears to be associated with higher mortality and disability, independently of mean BP levels within the first 24 h post EVT. BPV in the first 24 h may be a novel target to improve outcomes after EVT for AIS.

Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial.

BACKGROUND: People with factor XI deficiency have lower rates of ischaemic stroke than the general population and infrequent spontaneous bleeding, suggesting that factor XI has a more important role in thrombosis than in haemostasis. Milvexian, an oral small-molecule inhibitor of activated factor XI, added to standard antiplatelet therapy, might reduce the risk of non-cardioembolic ischaemic stroke without increasing the risk of bleeding. We aimed to estimate the dose-response of milvexian for recurrent ischaemic cerebral events and major bleeding in patients with recent ischaemic stroke or transient ischaemic attack (TIA). METHODS: AXIOMATIC-SSP was a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial done at 367 hospitals in 27 countries. Eligible participants aged 40 years or older, with acute (<48 h) ischaemic stroke or high-risk TIA, were randomly assigned by a web-based interactive response system in a 1:1:1:1:1:2 ratio to receive one of five doses of milvexian (25 mg once daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, or 200 mg twice daily) or matching placebo twice daily for 90 days. All participants received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg daily for the first 90 days. Investigators, site staff, and participants were masked to treatment assignment. The primary efficacy endpoint was the composite of ischaemic stroke or incident covert brain infarct on MRI at 90 days, assessed in all participants allocated to treatment who completed a follow-up MRI brain scan, and the primary analysis assessed the dose-response relationship with Multiple Comparison Procedure-Modelling (MCP-MOD). The main safety outcome was major bleeding at 90 days, assessed in all participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT03766581) and the EU Clinical Trials Register (2017-005029-19). FINDINGS: Between Jan 27, 2019, and Dec 24, 2021, 2366 participants were randomly allocated to placebo (n=691); milvexian 25 mg once daily (n=328); or twice-daily doses of milvexian 25 mg (n=318), 50 mg (n=328), 100 mg (n=310), or 200 mg (n=351). The median age of participants was 71 (IQR 62-77) years and 859 (36%) were female. At 90 days, the estimates of the percentage of participants with either symptomatic ischaemic stroke or covert brain infarcts were 16·8 (90·2% CI 14·5-19·1) for placebo, 16·7 (14·8-18·6) for 25 mg milvexian once daily, 16·6 (14·8-18·3) for 25 mg twice daily, 15·6 (13·9-17·5) for 50 mg twice daily, 15·4 (13·4-17·6) for 100 mg twice daily, and 15·3 (12·8-19·7) for 200 mg twice daily. No significant dose-response was observed among the five milvexian doses for the primary composite efficacy outcome. Model-based estimates of the relative risk with milvexian compared with placebo were 0·99 (90·2% CI 0·91-1·05) for 25 mg once daily, 0·99 (0·87-1·11) for 25 mg twice daily, 0·93 (0·78-1·11) for 50 mg twice daily, 0·92 (0·75-1·13) for 100 mg twice daily, and 0·91 (0·72-1·26) for 200 mg twice daily. No apparent dose-response was observed for major bleeding (four [1%] of 682 participants with placebo, two [1%] of 325 with milvexian 25 mg once daily, two [1%] of 313 with 25 mg twice daily, five [2%] of 325 with 50 mg twice daily, five [2%] of 306 with 100 mg twice daily, and five [1%] of 344 with 200 mg twice daily). Five treatment-emergent deaths occurred, four of which were considered unrelated to the study drug by the investigator. INTERPRETATION: Factor XIa inhibition with milvexian, added to dual antiplatelet therapy, did not substantially reduce the composite outcome of symptomatic ischaemic stroke or covert brain infarction and did not meaningfully increase the risk of major bleeding. Findings from our study have informed the design of a phase 3 trial of milvexian for the prevention of ischaemic stroke in patients with acute ischaemic stroke or TIA. FUNDING: Bristol Myers Squibb and Janssen Research & Development.

Update on the INTEnsive ambulance-delivered blood pressure Reduction in hyper-ACute stroke Trial (INTERACT4): progress and baseline features in 2053 participants.

BACKGROUND AND AIMS: Uncertainty persists over the effects of blood pressure (BP) lowering in acute stroke. The INTEnsive ambulance-delivered blood pressure Reduction in hyper-Acute stroke Trial (INTERACT4) aims to determine efficacy and safety of hyperacute intensive BP lowering in patients with suspected acute stroke. Given concerns over the safety of this treatment in the pre-hospital setting, particularly in relation to patients with intracerebral hemorrhage, we provide an update on progress of the study and profile of participants to date. METHODS: INTERACT4 is an ongoing multicentre, ambulance-delivered, randomized, open-label, blinded endpoint trial of pre-hospital BP lowering in patients with suspected acute stroke and elevated BP in China. Patients are randomized via a mobile phone digital system to intensive (target systolic BP [SBP] <140mmHg within 30 min) or guideline-recommended BP management. Primary outcome is an ordinal analysis of the full range of scores on the modified Rankin scale scores at 90 days. RESULTS: Between March 2020 and April 2023, 2053 patients (mean age 70 years, female 39%) were recruited with a mean BP 178/98 mmHg in whom 45% have a diagnosis of primary intracerebral hemorrhage upon arrival at hospital. At the time of presentation to hospital, the mean SBP was 160 and 170mmHg in the intensive and control groups (Δ10 mmHg), respectively. The independent data and safety monitoring board has not identified any safety concerns and recommended continuation of the trial. The sample size was reduced from 3116 to 2320 after meetings in August 2022 as the stroke mimic rate was persistently lower than initially estimated (6% vs 30%). The study is expected to be completed in late 2023 and the results announced in May 2024. CONCLUSIONS: INTERACT4 is on track to provide reliable evidence of the effectiveness of ambulance-delivered intensive BP lowering in patients with suspected acute stroke. TRIAL REGISTRATION: ClinicalTrials.gov NCT03790800 ; registered on 2 January 2019. Chinese Trial Registry ChCTR1900020534 , registered on 7 January 2019.

Prehospital screening of acute stroke with the National Institutes of Health Stroke Scale (ParaNASPP): a stepped-wedge, cluster-randomised controlled trial.

BACKGROUND: Timely treatment of acute stroke depends on early identification and triage. Improved methods for recognition of stroke in the prehospital setting are needed. We aimed to assess whether use of the National Institutes of Health Stroke Scale (NIHSS) by paramedics in the ambulance could improve communication with the hospital, augment triage, and enhance diagnostic accuracy of acute stroke. METHODS: The Paramedic Norwegian Acute Stroke Prehospital Project (ParaNASPP) was a stepped-wedge, single-blind, cluster-randomised controlled trial. Patients with suspected acute stroke, who were evaluated by paramedics from five ambulance stations in Oslo, Norway, were eligible for inclusion. The five ambulance stations (defined as clusters) all initially managed patients according to a standard stroke protocol (control group), with randomised sequential crossover of each station to the intervention group. The intervention consisted of supervised training on NIHSS scoring, a mobile application to aid scoring, and standardised communication with stroke physicians. Random allocation was done via a simple lottery draw by administrators at Oslo University Hospital, who were independent of the research team. Allocation concealment was not possible due to the nature of the intervention. The primary outcome was the positive predictive value (PPV) for prehospital identification of patients with a final discharge diagnosis of acute stroke, analysed by intention to treat. Prespecified secondary safety outcomes were median prehospital on-scene time and median door-to-needle time. This trial is registered with ClinicalTrials.gov, NCT04137874, and is completed. FINDINGS: Between June 3, 2019, and July 1, 2021, 935 patients were evaluated by paramedics for suspected acute stroke. 134 patients met exclusion criteria or did not consent to participate. The primary analysis included 447 patients in the intervention group and 354 in the control group. There was no difference in PPV for prehospital identification of patients with a final discharge diagnosis of acute stroke between the intervention group (48·1%, 95% CI 43·4-52·8) and control group (45·8%, 40·5-51·1), with an estimated percentage points difference between groups of 2·3 (95% CI -4·6 to 9·3; p=0·51). Median prehospital on-scene time increased by 5 min in the intervention group (29 min [IQR 23-36] vs 24 min [19-31]; p<0·0001), whereas median door-to-needle time was similar between groups (26 min [21-36] vs 27 min [20-36]; p=0·90). No prehospital deaths were reported in either group. INTERPRETATION: The intervention did not improve diagnostic accuracy in patients with suspected stroke. A general increase in prehospital time during the pandemic and the identification of smaller strokes that require more deliberation are possible explanations for the increased on-scene time. The ParaNASPP model is to be implemented in Norway from 2023, and will provide real-life data for further research. FUNDING: Norwegian Air Ambulance Foundation and Oslo University Hospital.

Endovascular treatment for large-core ischaemic stroke: a meta-analysis of randomised controlled clinical trials.

BACKGROUND AND PURPOSE: Current guidelines recommend endovascular treatment (EVT) for acute ischaemic stroke (AIS), due to large-vessel occlusion and an Alberta Stroke Program Early CT Score (ASPECTS) of ≥6. High-quality evidence resulting from randomised controlled clinical trials (RCTs) regarding EVT among large-core AIS has recently become available, justifying an updated meta-analysis aiming to evaluate efficacy and safety of EVT in this clinical setting. METHODS: We conducted a systematic review and meta-analysis including all available RCTs that compared EVT in addition to best medical treatment (BMT) versus BMT alone for large-core AIS (defined by ASPECTS 2-5 or volumetric methods). The primary outcome was reduced disability at 3 months (≥1-point reduction across all Modified Rankin Scale (mRS) grades). Secondary outcomes included independent ambulation at 3 months (mRS score 0-3), good functional outcome at 3 months (mRS score 0-2), excellent functional outcome at 3 months (mRS score 0-1), symptomatic intracranial haemorrhage (sICH) and any intracranial haemorrhage (ICH) and mortality at 3 months. The random-effects model was used. RESULTS: Four RCTs were included comprising a total of 662 patients treated with EVT vs 649 patients treated with BMT. Compared with BMT, EVT was significantly associated with reduced disability (common OR 1.70, 95% CI 1.39 to 2.07; I2=0%), independent ambulation (risk ratio (RR) 1.69, 95% CI 1.33 to 2.14; I2=39%) and good functional outcome (RR 2.33, 95% CI 1.76 to 3.10; I2=0%), but not with excellent functional outcome (RR 1.46, 95% CI 0.91 to 2.33; I2=39%) at 3 months. Although rates of sICH (RR 1.98, 95% CI 1.07 to 3.68; I2=0%) and any ICH (RR 2.13, 95% CI 1.70 to 2.66; I2=37%) were higher in the EVT group, 3-month mortality (RR 0.98, 95% CI 0.83 to 1.15; I2=0%) did not differ between the two groups. CONCLUSION: EVT appears to be effective and safe and may be considered for the treatment of large-core AIS, as assessed by ASPECTS of 2-5 or volumetric methods. PROSPERO REGISTRATION NUMBER: CRD42022334417.

Early versus Later Anticoagulation for Stroke with Atrial Fibrillation.

BACKGROUND: The effect of early as compared with later initiation of direct oral anticoagulants (DOACs) in persons with atrial fibrillation who have had an acute ischemic stroke is unclear. METHODS: We performed an investigator-initiated, open-label trial at 103 sites in 15 countries. Participants were randomly assigned in a 1:1 ratio to early anticoagulation (within 48 hours after a minor or moderate stroke or on day 6 or 7 after a major stroke) or later anticoagulation (day 3 or 4 after a minor stroke, day 6 or 7 after a moderate stroke, or day 12, 13, or 14 after a major stroke). Assessors were unaware of the trial-group assignments. The primary outcome was a composite of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death within 30 days after randomization. Secondary outcomes included the components of the composite primary outcome at 30 and 90 days. RESULTS: Of 2013 participants (37% with minor stroke, 40% with moderate stroke, and 23% with major stroke), 1006 were assigned to early anticoagulation and 1007 to later anticoagulation. A primary-outcome event occurred in 29 participants (2.9%) in the early-treatment group and 41 participants (4.1%) in the later-treatment group (risk difference, -1.18 percentage points; 95% confidence interval [CI], -2.84 to 0.47) by 30 days. Recurrent ischemic stroke occurred in 14 participants (1.4%) in the early-treatment group and 25 participants (2.5%) in the later-treatment group (odds ratio, 0.57; 95% CI, 0.29 to 1.07) by 30 days and in 18 participants (1.9%) and 30 participants (3.1%), respectively, by 90 days (odds ratio, 0.60; 95% CI, 0.33 to 1.06). Symptomatic intracranial hemorrhage occurred in 2 participants (0.2%) in both groups by 30 days. CONCLUSIONS: In this trial, the incidence of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death at 30 days was estimated to range from 2.8 percentage points lower to 0.5 percentage points higher (based on the 95% confidence interval) with early than with later use of DOACs. (Funded by the Swiss National Science Foundation and others; ELAN ClinicalTrials.gov number, NCT03148457.).