Sex-Based Analysis of Treatment, Time Metrics and Outcomes in Acute Ischemic Stroke Patients Treated in the Netherlands.

Introduction Sex disparities in stroke treatment have gained increasing interest, especially since women have worse post-stroke functional outcomes compared with men. Existing studies provide conflicting evidence, with some indicating women have longer delays and less often receive acute treatment, whereas others show no differences between men and women. We aimed to explore sex differences in acute treatment modalities and time metrics of patients with acute ischemic stroke (AIS) in a real-world setting. Secondly, we examined whether functional outcomes differed by sex and whether this was influenced by treatment timing. Methods We analyzed data from the Dutch Acute Stroke Audit, a prospective consecutive registry of AIS patients from 72 hospitals in the Netherlands, between 2017 and 2020. We captured data on type of treatment administered (intravenous thrombolysis [IVT] and endovascular thrombectomy [EVT]), time metrics (onset-to-door time [OTDT], door-to-needle and door-to-groin times), and functional outcomes at three months (modified Rankin scale [mRS]). The association between sex and poor outcome (mRS 3-6) was assessed with Cox proportional hazard models stratified by type of treatment and adjusted for age, additionally for National Institute of Health Stroke Scale (NIHSS) and OTDT. Results Of the 58,632 patients, 26,941 (46%) were women. Compared with men, women were, older (mean age 74.6 versus 71.0, p<.001) and presented with slightly higher NIHSS-scores (median 3 [IQR 2-7] versus 3 [IQR 1-6], p<.001). Treatment modalities distribution (no treatment, IVT, EVT) was similar between women and men (64%; 29%; 10% versus 63%; 30%; 9%, p=.16). Women had a slightly longer OTDT (median 145 versus 139 minutes, p<.01). Women had increased odds of poor outcomes (OR 1.49 [95%CI 1.34-1.56]). This was still statistically significant after adjusting for age and NIHSS-score (OR 1.22 [95%CI 1.16-1.28]). Neither treatment modality nor OTDT had an additional influence on this association. Conclusion In this large real-world registry, we observed no differences in distribution of treatment modalities between sexes. We did find a minor pre-hospital delay in women and worse functional outcomes in women. The minor delay in OTDT does not fully explain the observed worse outcomes in women. Our results provide reassurance that no major sex biases are apparent in acute stroke management throughout participating Dutch centers.

Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial.

BACKGROUND: Platelet transfusion after acute spontaneous primary intracerebral haemorrhage in people taking antiplatelet therapy might reduce death or dependence by reducing the extent of the haemorrhage. We aimed to investigate whether platelet transfusion with standard care, compared with standard care alone, reduced death or dependence after intracerebral haemorrhage associated with antiplatelet therapy use. METHODS: We did this multicentre, open-label, masked-endpoint, randomised trial at 60 hospitals in the Netherlands, UK, and France. We enrolled adults within 6 h of supratentorial intracerebral haemorrhage symptom onset if they had used antiplatelet therapy for at least 7 days beforehand and had a Glasgow Coma Scale score of at least 8. With use of a secure web-based system that concealed allocation and used biased coin randomisation, study collaborators randomly assigned participants (1:1; stratified by hospital and type of antiplatelet therapy) to receive either standard care or standard care with platelet transfusion within 90 min of diagnostic brain imaging. Participants and local investigators giving interventions were not masked to treatment allocation, but allocation was concealed from outcome assessors and investigators analysing data. The primary outcome was shift towards death or dependence rated on the modified Rankin Scale (mRS) at 3 months, and analysed by ordinal logistic regression, adjusted for stratification variables and the Intracerebral Haemorrhage Score. The primary analysis was done in the intention-to-treat population and safety analyses were done in the intention-to-treat and as-treated populations. This trial is registered with the Netherlands Trial Register, number NTR1303, and is now closed. FINDINGS: Between Feb 4, 2009, and Oct 8, 2015, 41 sites enrolled 190 participants. 97 participants were randomly assigned to platelet transfusion and 93 to standard care. The odds of death or dependence at 3 months were higher in the platelet transfusion group than in the standard care group (adjusted common odds ratio 2·05, 95% CI 1·18-3·56; p=0·0114). 40 (42%) participants who received platelet transfusion had a serious adverse event during their hospital stay, as did 28 (29%) who received standard care. 23 (24%) participants assigned to platelet transfusion and 16 (17%) assigned to standard care died during hospital stay. INTERPRETATION: Platelet transfusion seems inferior to standard care for people taking antiplatelet therapy before intracerebral haemorrhage. Platelet transfusion cannot be recommended for this indication in clinical practice. FUNDING: The Netherlands Organisation for Health Research and Development, Sanquin Blood Supply, Chest Heart and Stroke Scotland, French Ministry of Health.

Medical Treatment for Spontaneous Anticoagulation-Related Intracerebral Hemorrhage in the Netherlands.

BACKGROUND: Spontaneous anticoagulation-related intracerebral hemorrhage accounts for up to a quarter of spontaneous intracerebral hemorrhage cases and is associated with higher hematoma volume and a worse outcome. Guidelines recommend rapid anticoagulant reversal but mode and timing are not specified and optimal strategy is uncertain. Variability in everyday practice is unknown. METHODS: An invitation to a web-based survey was sent to 85 Dutch stroke neurologists in different hospitals, with questions about importance, timing, and medical management of spontaneous anticoagulation-related intracerebral hemorrhage. RESULTS: In total, 61 (72%) neurologists completed the survey. Nearly all (97%) deemed rapid anticoagulant reversal important. A local guideline for management of anticoagulant reversal was used in 80% of the hospitals. Most neurologists (56%) estimated anticoagulant reversal in anticoagulation-related intracerebral hemorrhage to start later than intravenous thrombolysis in ischemic stroke. Few (5%) thought it was quicker. A minority (28%) of the hospitals started anticoagulation reversal without waiting for laboratory test results or consulting a specialist in hemostasis. Prothrombin complex concentrate was used by all neurologists for vitamin K antagonist reversal and by most (74%) for reversal of thrombin inhibitors and factor Xa inhibitors (72%). Anticoagulation reversal was initiated at the emergency department according to 89% of the respondents. CONCLUSION: Variability in logistics in acute management of spontaneous anticoagulation-related intracerebral hemorrhage was demonstrated. Anticoagulant reversal is deemed important, but is estimated to have a longer door-to-needle time than alteplase in thrombolysis for ischemic stroke by most neurologists. Several delaying factors were found. These factors might have an impact on outcome.

Intracerebral Haemorrhage Segmentation in Non-Contrast CT.

A 3-dimensional (3D) convolutional neural network is presented for the segmentation and quantification of spontaneous intracerebral haemorrhage (ICH) in non-contrast computed tomography (NCCT). The method utilises a combination of contextual information on multiple scales for fast and fully automatic dense predictions. To handle a large class imbalance present in the data, a weight map is introduced during training. The method was evaluated on two datasets of 25 and 50 patients respectively. The reference standard consisted of manual annotations for each ICH in the dataset. Quantitative analysis showed a median Dice similarity coefficient of 0.91 [0.87-0.94] and 0.90 [0.85-0.92] for the two test datasets in comparison to the reference standards. Evaluation of a separate dataset of 5 patients for the assessment of the observer variability produced a mean Dice similarity coefficient of 0.95 ± 0.02 for the inter-observer variability and 0.97 ± 0.01 for the intra-observer variability. The average prediction time for an entire volume was 104 ± 15 seconds. The results demonstrate that the method is accurate and approaches the performance of expert manual annotation.

Acute Management of Hemostasis in Patients With Neurological Injury.

Neurological injuries can be divided into those with traumatic and nontraumatic causes. The largest groups are traumatic brain injury (TBI) and nontraumatic stroke. TBI patients may present with intracranial hemorrhages (contusions, or subdural or epidural hematomas). Strokes are ischemic or hemorrhagic. In all these disorders, thrombosis and hemostasis play a major role. Treatment aims to either cease bleeding and/or restore perfusion. We reviewed hemostatic and thrombolytic therapies in patients with neurological injuries by MEDLINE and EMBASE search using various key words for neurological disorders and hemostatic therapies restricted to English language and human adults. Review of articles fulfilling inclusion criteria and relevant references revealed that, in patients with ischemic stroke, intravenous thrombolytic therapy with recombinant tissue plasminogen activator within 4.5-5 hours after onset of symptoms improves clinical outcome. In contrast, there are no hemostatic therapies that are proven to improve clinical outcome of patients with hemorrhagic stroke or TBI. In patients with hemorrhagic stroke who use vitamin K antagonist or direct oral anticoagulants, there is evidence that specific reversal therapies improve hemostatic laboratory parameters but without an effect on clinical recovery. In patients with hemorrhagic stroke or TBI who use concomitant antiplatelet therapy, there is evidence for harm of platelet transfusion. In patients with aneurysmal subarachnoid hemorrhage, tranexamic acid was shown to reduce rebleeding rate without improving clinical outcome. The effects of tranexamic acid in patients with TBI are still under investigation. We conclude that, in patients with ischemic stroke, thrombolytic therapy improves outcome when given within 4.5-5 hours. In hemorrhagic stroke and TBI, most hemostatic therapies improved or corrected laboratory parameters but not clinical outcome. Currently, in several trials, the effects of tranexamic acid are being studied of which the results are eagerly awaited. Because improving clinical outcome should be the goal of new therapies, we encourage to use clinical outcome scales as the primary outcome measure in trials that investigate effects of hemostatic therapies in patients with neurological injury.

Statistical analysis plan for the PlAtelet Transfusion in Cerebral Haemorrhage (PATCH) trial: a multicentre randomised controlled trial.

BACKGROUND: Use of antiplatelet therapy shortly before stroke due to spontaneous primary intracerebral haemorrhage (ICH) is associated with higher case fatality in comparison to ICH without prior antithrombotic drug use. The PlAtelet Transfusion in Cerebral Haemorrhage (PATCH) trial aimed to assess the effect of platelet transfusion in patients presenting with ICH while using antiplatelet therapy. The main hypothesis of PATCH was that platelet transfusion would reduce death or dependence by reducing ICH growth. METHODS/DESIGN: PATCH was a multicentre prospective, randomised, open, blinded endpoint (PROBE) parallel group trial, conducted at 60 hospitals in The Netherlands, Scotland and France. Forty-one sites enrolled 190 patients with spontaneous supratentorial ICH aged ≥18 years, who had used antiplatelet therapy for ≥7 days preceding ICH, if Glasgow Coma Scale was ≥8. Participants were randomised (1:1, with a secure web-based system using permuted blocks, stratified by study centre and type of antiplatelet therapy pre-ICH) to receive either platelet transfusion within 6 hours of symptom onset and 90 minutes of diagnostic brain imaging, or standard care without platelet transfusion. The primary outcome was modified Rankin Scale (mRS) score assessed blind to treatment allocation at 3 months after ICH. Planned secondary outcomes included ICH growth on brain imaging performed approximately 24 hours after randomisation, survival at 3 months, disability at 3 months scored using the Amsterdam Medical Centre linear disability score, heterogeneity of treatment effect on mRS and ICH growth according to presence of the computed tomography angiography spot sign, causes of poor outcome, and cost-effectiveness. Safety outcomes were transfusion reactions, thromboembolic complications, and serious adverse events occurring during hospitalisation. This statistical analysis plan was written without knowledge of the unblinded data. TRIAL REGISTRATION: The trial was registered with the Netherlands Trial Register on 29 April 2008 ( NTR1303 ).