by Viktoria Papp
Each month the EANpages editorial team reviews the scientific press for recently published papers of outstanding interest to neurologists. Below we present our selection for February 2024 (for our Paper of the Month for February, see here).
1. Argatroban in Patients with Acute Ischemic Stroke with Early Neurological Deterioration: A Randomized Clinical Trial
This prospective, multicentre, open-label, blinded–endpoint, randomised (1:1) clinical trial assessed the efficacy and safety of argatroban in combination with antiplatelet therapy for early neurological deterioration (END) within 48 hours after symptom onset in a Chinese population. Argatroban is a direct rapid and short-acting thrombin inhibitor with low bleeding rates. Adult patients (age >18 years) with acute ischaemic stroke experiencing END were included between 4 April 2020 and 31 July 2022. END was defined as an increase in the total National Institutes of Health Stroke Scale (NIHSS) by 2 or more points within 48 hours after symptom onset. The primary outcome was a good functional outcome (modified Rankin Scale [mRS]: 0-3) after 90 days. The secondary outcomes were an mRS score of 0-2 as well as a shift in mRS at 90 days, NIHSS score at 7 days and 90 days±3 days, Barthel scale score at 90±3days, and cardiovascular events at 90±3days. The standard therapy was antiplatelet therapy with aspirin and/or clopidogrel in both the control and argatroban groups. In addition to the standard therapy, the argatroban group also received 7-days intravenous argatroban treatment.Among the randomized 628 patients, the mean age was 65 (SD: ± 11.9) years and 63.7% were male.The results showed that the percentage of patients with an mRS score of 0-3 at 90 days was 80.5% in the argatroban group compared to 73.3% in the control group, giving a significant unadjusted risk difference of 7.2 (95% CI: 0.6-14.0) and a risk ratio of 1.10 (95% CI: 1.01-1.20), p=0.04. After adjusting for prespecified prognostic variables the results remained significantly different in favour of the argatroban group. Among the secondary outcomes, the only significant difference was found in the proportion of patients in the different mRS scores at 90 days. Side effects occurred equally in the two groups; symptomatic intracranial haemorrhage was reported in 0.9% of the argatroban group and 0.7% of the control group (p=0.78). This trial revealed that the combination of argatroban and the standard antiplatelet therapy can lead to a higher likelihood of good functional outcome at 90 days in patients with stroke in progression.
2. Clinical descriptors of disease trajectories in patients with traumatic brain injury in the intensive care unit (CENTER-TBI): a multicentre observational cohort study
Thisinternational prospective observational cohort study included adult patients (age >18 years) admitted to an intensive care unit due to traumatic brain injury from 54 participating centres to identify and distinguish different disease trajectories and outcomes with clustering method applying a mix of probabilistic graph models to group patients according to baseline and longitudinal variables. The candidate variables were pre-injury data and injury features, clinical characteristics on admission, demographics, physiological parameters, laboratory features, brain protein biomarkers (ubiquitin carboxyterminal hydrolase L1 [UCH-L1], S100 calcium-binding protein B [S100B], tau, neurofilament light [NFL], glial fibrillary acidic protein [GFAP], and neuron-specific enolase [NSE]), and interventions during the first 7 days of admission. In the study period from 19 December 2014 to 17 December 2017, 1728 patients were eligible for inclusion in the final analysis. The median Glasgow Coma Scale (GCS) score at admission was 9 (IQR 4–14). Twenty-two per cent of the patients died, and 45.1% had unfavorable outcomes (defined as upper severe disability or worse, extended Glasgow Outcome Scale [GOS-E] ≤4). The median age was 52 years (IQR 33–67) and 73.4% of the patients were male. The results showed that key variables that contributed to defining different disease trajectories during the first week of ICU admission were glycaemic variation, and brain biomarkers (tau, UCH-L1, GFAP, S100B, NSE, and NFL). While mean intracranial pressure, CSF drainage volume, creatinine, sodium variation, and oxygen saturation were important for disease trajectories in the first 3 days. They defined six disease trajectories in this study that were different in 6-month mortality and GOS-E score. This cluster of variables suggesting disease trajectories in traumatic brain injury could play a role in future targeted treatment approaches.
3. Apixaban versus Aspirin for Embolic Stroke of Undetermined Source
This investigator-initiated multicentre, randomised, open-label, blinded-outcome trial conducted in Germany aimed to evaluate the efficacy of apixaban compared to aspirin in selected patients with embolic stroke of undetermined source (ESUS) who have known risk factors for cardioembolism – ESUS with “enrichment factors” – such as predictive for atrial fibrillation or patent foramen ovale. Participants were randomised (1:1) to receive either 5mg of apixaban twice daily or 100mg of aspirin once daily. The primary endpoint was any new ischaemic lesion on brain MRI at 12-month follow-up compared to baseline. Among the secondary endpoints were composites of major adverse cardiovascular events, recurrent stroke, major and clinically relevant nonmajor bleeding, quality of life, and cognitive and physical assessment during the 12-month follow-up period. From 16 German stroke centres, 353 patients were included between January 2016 and August 2020. The mean age was 68.4 (SD: 10.5) years and 48.6% were female. New ischaemic lesions were found in 13.6% of patients in the apixaban group and 16.0% of patients in the aspirin group (adjusted odds ratio, 0.79; 95% CI: 0.42-1.48; p=0.57). There was no significant difference between the groups regarding the occurrence of bleeding, other severe side effects, or in any other secondary endpoints. In conclusion, this trial did not find direct apixaban treatment superior to cardiac monitoring-guided aspirin in the prevention of new ischaemic lesions in patients with ESUS with “enrichment factors”.
4. 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
This phase-2 dose-finding trial tested milvaxian, an inhibitor of activated factor XI in secondary stroke prevention. Factor XI was shown to be important in thrombus evolvement while less crucial in haemostasis; thereby, inhibition of factor XI may be an effective and safe anticoagulation. The primary aim of the study was to assess the dose–response effect of milvexian compared to placebo regarding the incidence of symptomatic ischaemic stroke and covert brain infarction at 90 days. Secondarily, to evaluate the potential bleeding risk at 90 days. The patients aged 40 years or older included in the study had acute non-cardioembolic ischaemic stroke (< 48 hours) or high-risk transient ischaemic attack. They were randomised (1:1:1:1:1:2) into one of the five dose groups of the study drug or to placebo. In total, 2366 patients were randomised to either placebo (n=691) or one of five doses of milvexian (n=1635) between 27 January 2019, and 24 December 2021, however, 585 (25%)of them did not complete the 90-day treatment phase (placebo: 23% vs. milvexian group: 25%); some due to side effects (placebo: 12% vs. milvexian group: 26%). The percentage of patients who suffered either symptomatic ischaemic stroke or covert brain infarcts was 16.8% for placebo, 16.7% for 25mg milvexian once daily, 16.6% for 25mg twice daily, 15.6% for 50mg twice daily, 15.4% for 100mg twice daily, and 15.3 for 200mg twice daily. There was no significant dose–response among the five milvexian doses for the primary outcome. The risk of intracerebral bleeding was not different among the groups. Inhibition of activated factor XI with milvexian neither considerably reduced the risk of symptomatic ischaemic stroke or covert brain infarction nor increased the risk of severe bleeding.
