Rationale and design of the AXIOMATIC-SSP phase II trial: Antithrombotic treatment with factor XIa inhibition to Optimize Management of Acute Thromboembolic events for Secondary Stroke Prevention

MRI; Milvexian; Stroke preventionResonancia magnética; Milvexian; Prevención de ictusRessonància magnètica; Milvexian; Prevenció d'ictusBackground Individuals with ischemic stroke or transient ischemic attack (TIA) have a high early risk of ischemic stroke despite dual antiplatelet therapy. The risk of ischemic stroke, and associated disability, represents a significant unmet clinical need. Genetic variants resulting in reduced factor XI levels are associated with reduced risk for ischemic stroke but are not associated with increased intracranial bleeding. Milvexian is an oral small-molecule inhibitor of FXIa that binds activated factor XI with high affinity and selectivity and may reduce the risk of stroke when added to antiplatelet drugs without significant bleeding. We aimed to evaluate the dose-response relationship of milvexian in participants treated with dual antiplatelets. Methods We began a phase II, double-blinded, randomized, placebo-controlled trial at 367 sites in 2019. Participants (N = 2366) with ischemic stroke (National Institutes of Health Stroke Scale score ≤7) or high-risk TIA (ABCD2 score ≥6) were randomized to 1 of 5 doses of milvexian or placebo for 90 days. Participants also received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg for 90 days. The efficacy endpoint was the composite of ischemic stroke or incident infarct on magnetic resonance imaging. Major bleeding, defined as type 3 or 5 bleeding according to the Bleeding Academic Research Consortium, was the safety endpoint. Participant follow-up will end in 2022. Conclusion The AXIOMATIC-SSP trial will evaluate the dose-response of milvexian for ischemic stroke occurrence in participants with ischemic stroke or TIA.This study is sponsored by Bristol Myers Squibb and Janssen Research & Development, LLC

Predictors and outcomes of neurological deterioration in intracerebral hemorrhage: results from the TICH-2 randomised controlled trial

Neurological deterioration is common after intracerebral hemorrhage (ICH). We aimed to identify the predictors and effects of neurological deterioration and whether tranexamic acid reduced the risk of neurological deterioration. Data from the Tranexamic acid in IntraCerebral Hemorrhage-2 (TICH-2) randomized controlled trial were analyzed. Neurological deterioration was defined as an increase in National Institutes of Health Stroke Scale (NIHSS) of ≥ 4 or a decline in Glasgow Coma Scale of ≥ 2. Neurological deterioration was considered to be early if it started ≤ 48 h and late if commenced between 48 h and 7 days after onset. Logistic regression was used to identify predictors and effects of neurological deterioration and the effect of tranexamic acid on neurological deterioration. Of 2325 patients, 735 (31.7%) had neurological deterioration: 590 (80.3%) occurred early and 145 (19.7%) late. Predictors of early neurological deterioration included recruitment from the UK, previous ICH, higher admission systolic blood pressure, higher NIHSS, shorter onset-to-CT time, larger baseline hematoma, intraventricular hemorrhage, subarachnoid extension and antiplatelet therapy. Older age, male sex, higher NIHSS, previous ICH and larger baseline hematoma predicted late neurological deterioration. Neurological deterioration was independently associated with a modified Rankin Scale of > 3 (aOR 4.98, 3.70–6.70; p [less than] 0.001). Tranexamic acid reduced the risk of early (aOR 0.79, 0.63–0.99; p = 0.041) but not late neurological deterioration (aOR 0.76, 0.52–1.11; p = 0.15). Larger hematoma size, intraventricular and subarachnoid extension increased the risk of neurological deterioration. Neurological deterioration increased the risk of death and dependency at day 90. Tranexamic acid reduced the risk of early neurological deterioration and warrants further investigation in ICH

Relationship between nitrate headache and outcome in patients with acute stroke: results from the efficacy of nitric oxide in stroke (ENOS) trial

IntroductionNitrate-induced headache is common and may signify responsive cerebral vasculature. We assessed the relationship between nitrate-headache and outcome in patients with acute stroke.Materials and MethodsPatients were those randomised to glyceryl trinitrate (GTN) versus no GTN in the Efficacy of Nitric Oxide in Stroke trial. Development of headache by end of treatment (day 7), and functional outcome (modified Rankin Scale, mRS, primary outcome) at day 90, were assessed. Analyses are adjusted for baseline prognostic factors and give odds ratio (OR) and mean difference (MD) with 95% confidence intervals (95% CI).ResultsIn 4011 patients, headache was more common in GTN than control (360, 18.0% vs. 170, 8.5%; 2

Route of feeding as a proxy for dysphagia after stroke and the effect of transdermal glyceryl trinitrate: data from the efficacy of nitric oxide in stroke randomised controlled trial

Post-stroke dysphagia is common, associated with poor outcome and often requires non-oral feeding/fluids. The relationship between route of feeding and outcome, as well as treatment with glyceryl trinitrate (GTN), was studied prospectively. The Efficacy of Nitric Oxide in Stroke (ENOS) trial assessed transdermal GTN (5 mg versus none for 7 days) in 4011 patients with acute stroke and high blood pressure. Feeding route (oral = normal or soft diet; nonoral = nasogastric tube, percutaneous endoscopic gastrostomy tube, parenteral fluids, no fluids) was assessed at baseline and day 7. The primary outcome was the modified Rankin Scale (mRS) measured at day 90. At baseline, 1331 (33.2%) patients had non-oral feeding, were older, had more severe stroke and more were female, than 2680 (66.8%) patients with oral feeding. By day 7, 756 patients had improved from non-oral to oral feeding, and 119 had deteriorated. Non-oral feeding at baseline was associated with more impairment at day 7 (Scandinavian Stroke Scale 29.0 versus 43.7; 2p < 0.001), and worse mRS (4.0 versus 2.7; 2p < 0.001) and death (23.6 versus 6.8%; 2p = 0.014) at day 90. Although GTN did not modify route of feeding overall, randomisation ≤6 hours of stroke was associated with a move to more oral feeding at day 7 (odds ratio = 0.61, 95% confidence intervals 0.38, 0.98; 2p = 0.040). As a proxy for dysphagia, non-oral feeding is present in 33% of patients with acute stroke and associated with more impairment, dependency and death. GTN moved feeding route towards oral intake if given very early after stroke

Effect of glyceryl trinitrate on haemodynamics in acute stroke: data from the Efficacy of Nitric Oxide in Stroke trial

Background and Purpose: Increased blood pressure (BP), heart rate and their derivatives (variability, pulse pressure, rate-pressure product [RPP]) are associated with poor clinical outcome in acute stroke. We assessed the effects of glyceryl trinitrate (GTN) on haemodynamic parameters, and these on outcome in participants in the Efficacy of Nitric Oxide in Stroke trial.Methods: 4011 patients with acute stroke and raised BP were randomised within 48 hours of onset to transdermal GTN or no GTN for 7 days. Peripheral haemodynamics were measured at baseline (3 measures) and daily (2 measures) during treatment. Between-visit BP variability over days 1 to 7 (as standard deviation) was assessed in quintiles. Functional outcome was assessed as modified Rankin Scale (mRS) and cognition as telephone mini-mental state examination (t-MMSE) at day 90. Analyses were adjusted for baseline prognostic variables. Data are mean difference (MD) or odds ratios (OR) with 95% confidence intervals (CI).Results: Increased baseline BP (diastolic, variability), heart rate and RPP were each associated with unfavourable functional outcome at day 90. Increased between-visit systolic BP variability was associated with an unfavourable shift in mRS (highest quintile adjusted OR 1.65, 95% CI 1.37 to 1.99), worse cognitive scores (t-MMSE: highest quintile adjusted MD -2.03, 95% CI -2.84 to -1.22) and increased odds of death at day 90 (highest quintile adjusted OR 1.57, 95% CI 1.12 to 2.19). GTN lowered BP and RPP, and increased heart rate at day 1; and reduced between-visit systolic BP variability.Conclusions: Increased between-visit BP variability was associated with poor functional and cognitive outcomes and increased death 90 days after acute stroke. In addition to lowering BP and RPP, GTN reduced between-visit systolic BP variability. Agents that lower BP variability in acute stroke require further study

The COVID-19 pandemic and neurology: A survey on previous and continued restrictions for clinical practice, curricular training, and health economics

Background and Purpose The COVID-19 pandemic has significantly impacted health systems worldwide. Here, we assessed the pandemic's impact on clinical service, curricular training, and financial burden from a neurological viewpoint during the enforced lockdown periods and the assumed recovery by 2023. Methods An online 18-item survey was conducted by the European Academy of Neurology (EAN) NeuroCOVID-19 Task Force among the EAN community. The survey was online between February and March 2023. Questions related to general, demographic, clinical, work, education, and economic aspects. Results We collected 430 responses from 79 countries. Most health care professionals were aged 35–44 years, with >15 years of work experience. The key findings of their observations were as follows. (i) Clinical services were cut back in all neurological subspecialties during the most restrictive COVID-19 lockdown period. The most affected neurological subspecialties were services for patients with dementia, and neuromuscular and movement disorders. The levels of reduction and the pace of recovery were distinct for acute emergencies and in- and outpatient care. Recovery was slow for sleep medicine, autonomic nervous system disorders, neurorehabilitation, and dementia care. (ii) Student and residency rotations and grand rounds were reorganized, and congresses were converted into a virtual format. Conferences are partly maintained in a hybrid format. (iii) Affordability of neurological care and medication shortage are emerging issues. Conclusions Recovery of neurological services up to spring 2023 has been incomplete following substantial disruption of neurological care, medical education, and health economics in the wake of the COVID-19 pandemic. The continued limitations for the delivery of neurological care threaten brain health and call for action on a global scale

Rivaroxaban for secondary stroke prevention in patients with embolic strokes of undetermined source : Design of the NAVIGATE ESUS randomized trial

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