Hemorrhagic Transformation Research Articles

Abstract WP156: Temporal Changes in Blood Viscosity in Acute Ischemic Stroke and Its Relationship With Infarct Growth and Hemorrhagic Transformation

Background: Blood viscosity (BV) affects blood vessel wall shear stress. Yet, temporal changes of BV in acute stroke patients and correlation with infarct growth and hemorrhagic transformation remain unclear. Method: This prospective observational study included acute ischemic stroke patients admitted within 24h of the last known well time, who gave an informed consent and had adequate blood sampling. Consecutive BV measurements (at 10Hz) were taken upon admission (1 st ), at 24h (2 nd ), and between 5-7 days post-admission. Each patient underwent initial and follow-up MRI. Outcomes were 1) infarct growth or recurrence, and 2) increased hemorrhagic transformation (HT) in follow-up MRI compared to the initial MRI. We assessed whether the ratio of the 2nd BV to the 1st BV and 3 rd BV to the 1 st BV were associated with outcomes. Results: Twenty-six patients met eligible criteria and had adequate blood sampling. BV demonstrated a decreasing trend during the admission (1 st BV: median 20.2 [IQR 14.8-23.2], 2 nd BV: 17.9 [14.8-20.2], 3 rd BV: 15.3 [12.0-22.0]). The ratios of 2 nd BV to 1 st BV and 3 rd BV to 1 st BV decreased after admission (P=0.41 and P=0.015 with Wilcoxon rank test, respectively). While the ratio of 2 nd BV to 1 st BV between patients with and without increased HT (1.28 [1.04-1.41] vs. 0.89 [0.67-1.33], p=0.67 with Wilcoxon rank test) was similar, it showed a tendency to rise in patients with infarct growth or recurrence (1.25 [0.78-1.63] vs. 0.80 [0.66-1.21], P=0.11 with Wilcoxon rank test) (Figure). The ratio of 3 rd BV to 1 st BV was higher in patients with increased HT (0.96 [0.82-1.27] vs. 0.72 [0.59-0.81], P=0.25 with Wilcoxon rank test). Conclusion: BV at the 24h post-admission appears to correlate with infarct growth or recurrence during the acute stroke period. BV was likely to persistently increase in patients with HT. Further investigations with a larger dataset are recommended to elucidate the predictive value of 24h BV in acute stroke patients.

Abstract WP23: Hemorrhagic Transformation Following Anticoagulation in Victims of Acute Ischemic Stroke Secondary to Intra-Cardiac Thrombi

Introduction: Hemorrhagic transformation (HT) following acute ischemic stroke (AIS) is a common consideration especially when therapeutic anticoagulation is indicated in cases such as left ventricular or left atrial appendage thrombi. Although there have been multiple studies investigating the safe timing of anticoagulation initiation following AIS in patients with atrial fibrillation, the results varied. Evaluating the infarct volume and correlating it to time of anticoagulation initiation and HT can be detrimental to patient safety. Methods: We performed a retrospective review of all patients who were diagnosed with AIS secondary to cardio-embolic mechanisms and were admitted to our hospital between January 1, 2018, and December 31, 2022. The inclusion criteria consisted of patients aged 18 to 100 years who were found to have intra-cardiac thrombi and were initiated on anticoagulation within 80 hours of symptom onset. Infarct volume was measured using the ABC/2 formula. Statistical analysis was conducted using the R statistical program. For variables with a normal distribution, we used the mean and standard deviation (SD), and for variables with skewed distribution, we reported the median with interquartile range (IQR). Results: A total of 597 patient charts were reviewed for this study. After applying the inclusion criteria, 36 patients were deemed eligible for inclusion in the analysis. Among the included patients, a majority were male, constituting 80.6% (n=29) of the sample. The infarct volume among the included patients ranged from 0 ml to 100 ml. A breakdown of infarct volumes is as follows: Twenty-three patients (63.9%) had infarct volumes of 10 ml or less. Seven patients (19.4%) had infarct volumes ranging between 11 - 20 ml. Six patients (16.7%) had infarct volumes that exceeded 21 ml, with the largest infarct measuring 100 ml. There was no clinically significant HT. There were no surgical interventions required for any of our study subjects. Conclusion: The initiation of anticoagulation within 80 hours following AIS secondary to intra-cardiac thrombi may be safe, especially in patients with infarct volumes of 20 ml or less when using the ABC/2 formula.

CHinese Acute Tissue-Based Imaging Selection for Lysis In Stroke Tenecteplase II (CHABLIS-T II): rationale and design

Background and purposeTenecteplase (TNK) has demonstrated non-inferiority to alteplase in patients who had an acute ischaemic stroke presenting within 4.5 hours from symptom onset. The trial is aimed to explore...

Abstract TP200: Anticoagulation Use and Endovascular Thrombectomy in Patients With Large Core Stroke - A Secondary Analysis of SELECT2 Trial

Introduction: Anticoagulation (AC) use is common in patients presenting with acute ischemic stroke and is known to pose challenges to acute reperfusion therapy. However, evidence about association of AC use prior to stroke with endovascular thrombectomy outcomes and post-procedure hemorrhages, especially in those with large strokes is limited. Methods: From SELECT2, patients were stratified based on AC medication use and prior to stroke. Functional outcomes at 90day follow-up and hemorrhagic transformation on follow-up imaging were compared between patients with and without AC in adjusted regression models. Results: Of 352 patients, 29/180 (16%, VKA - 15, DOACs 14) EVT patients and 18/172 (10%, VKA - 3, DOACs 15) MM patients were receiving anticoagulants at baseline. AC patients were older (72 (62-79) y vs 66 (58-75) y), with higher cardiac morbidity (Congestive Heart Failure: 28% vs 10%, Atrial Fibrillation: 70% vs 17%), but had similar NIHSS [20 (16-24) vs 18 (15-23)], time to randomization [511 (350-909) vs 586 (326-920) minutes], CT ASPECTS [4 (3-5) vs 4 (3-5)] and ischemic core estimates [91 (71 -110) vs 103 (71-139) ml, AC vs nonAC respectively]. Within AC patients, EVT did not improve outcomes (Shift: 6 (4-6) vs 5 (4-6), aGenOR: 0.89 (0.53-1.50), mRS 0-3: 11% vs 14%, aRR: 1.27 (0.40-4.05), mRS 5-6: 69% vs 67%, aRR: 1.05 (0.73-1.50)]. Furthermore, EVT patients on AC reported numerically higher rates of any intracerebral hemorrhage [85.7% vs 70.2%, aRR: 1.18, 95% CI: 0.98-1.43], but no sICH or parenchymal hemorrhage and demonstrated worse outcome [median mRS: 6 (4-6) vs 4 (3-6), aGenOR: 0.49(0.32-0.74)], mRS 0-3: 14% vs 43%, aRR: 0.36 (0.15-0.86)], and mRS 5-6: 69% vs 43%, aRR: at 90 day follow-up and numerically lower functional independence (mRS 0-2) [3.4% vs 23.3%, aRR: 0.18(0.03-1.21)], AC vs nonAC respectively. Consistent results were observed in patients achieving successful reperfusion. Conclusion: Almost 1/7 th of patients presenting with large stroke in SELECT2 trial demonstrated AC use at baseline, with higher cardiac morbidity. These patients were more likely to have hemorrhagic outcomes and worse clinical outcomes after EVT and successful reperfusion. Clinicaltrials.gov registration: NCT03876457

Abstract 28: Patients Randomised to Glenzocimab Suffered Less Haemorrhagic Transformation at 24 Hours Compared to Placebo: AI-Imaging Sub-Analysis of the ACTIMIS Trial

Introduction: ACTIMIS (NCT03803007) was a randomized phase 1b/2a clinical trial evaluating glenzocimab, a monoclonal antibody fragment targeting platelet receptor glycoprotein VI in patients with acute ischemic stroke treated by thrombolysis. Primary analysis demonstrated a reduction in intracranial hemorrhage occurrence stroke-related mortality. In this sub-analysis, volumetric imaging biomarkers were used to assess efficacy of glenzocimab. Methods: In the phase 2a study, patients were randomized (1:1) with 1000mg glenzocimab or placebo. CT or MRI was acquired at baseline with CT at 24 hours and MRI at 7 days for safety and efficacy analysis. Baseline and follow up imaging were processed as post-hoc analysis using AI core lab software (Brainomix, Oxford, UK). Automated output was reviewed for accuracy by an expert clinician (DC) blinded to treatment allocation. Results and Conclusions: Follow up imaging data were available from 103/106 patients (51 glenzocimab, 52 placebo) at 24 hours. Of these, 54 underwent mechanical thrombectomy (MT, 27 glenzocimab, 27 placebo). Day-7 imaging was available for 9 fewer placebo patients and 1 glenzocimab patient. All except 2 patients (1 placebo, 1 glenzocimab) with missing data at Day-7 died during the study. Preliminary analysis showed smaller volume of hemorrhagic transformation (HT) in the glenzocimab group at 24 hours compared to placebo and a trend towards smaller volume of ischemic injury. Exploratory analysis also highlighted an interaction effect between risk of HT following MT and glenzocimab (lower risk in patients treated with glenzocimab). The full results of the imaging sub-analysis of the ACTIMIS study will be presented at the conference and discussed in the context of current literature.

WITHDRAWN: Malignant transformation of ischemic stroke in the era of mechanical thrombectomy: When is decompressive craniectomy required?

ObjectiveThe treatment of choice for ischemic stroke due to intracranial arterial occlusion of the anterior circulation has been mechanical thrombectomy (MT). The success rate of MT is described as 71%, but malignant infarction can nonetheless ensue. In these cases, decompressive craniectomy (DHC) is often necessary. To date, only few factors are known to correlate significantly with the need for DHC after MT. MethodsWe conducted a retrospective analysis of patients admitted with anterior circulation stroke at our department who underwent MT with and without subsequent DHC. Patients were matched according to ASPECT score on pre-MT CT scan. Established predictors for neurological outcome, TICI grade of recanalization, as well as imaging were then compared between the groups to elucidate which of them were predictive of DHC. ResultsA total of 86 patients were included in the analysis. DHC was performed in 43 patients (50%). In a univariate analysis, male sex (p = 0.037), lower TICI grade of recanalization (p < 0.001) and hemorrhagic transformation (p = 0.014) were predictive of DHC. Patients who received later intravenous thrombolysis were also at higher risk for needing DHC (p = 0.050). Patients suffering from hypercholesterolemia (p < .001) and who were on antiplatlet agents (p = .039) were at lower risk for needing DHC. ConclusionsPatients with higher rates of recanalization were protected against DHC. Later administration of IV tPA was correlated with DHC, thus suggesting a synergistic effect of IV tPA and MT in protecting against malignant transformation. Prior use of antiplatelet agents appears to be a protective factor against DHC in stroke, which warrants further investigation.

Comparison of brain imaging and physical health between research and clinical neuroimaging cohorts of ageing.

To compare brain MRI measures between Adult Changes in Thought (ACT) participants who underwent research, clinical, or both MRI scans, and clinical health measures across the groups and non-MRI subjects. Retrospective cohort study leveraging MRI, clinical, demographic, and medication data from ACT. Three neuroradiologists reviewed MRI scans using NIH Neuroimaging Common Data Elements (CDEs). Total brain and white matter hyperintensity (WMH) volumes, clinical characteristics, and outcome measures of brain and overall health were compared between groups. 1166 MRIs were included (77 research, 1043 clinical, and 46 both) and an additional 3146 participants with no MRI were compared. Compared to the group with research MRI only, the clinical MRI group had higher prevalence of the following: acute infarcts, chronic haematoma, subarachnoid haemorrhage, subdural haemorrhage, haemorrhagic transformation, and hydrocephalus (each P < .001). Quantitative WMH burden was significantly lower (P < .001) and total brain volume significantly higher (P < .001) in research MRI participants compared to other MRI groups. Prevalence of hypertension, self-reported cerebrovascular disease, congestive heart failure, dementia, and recent hospitalization (all P < .001) and diabetes (P = .002) differed significantly across groups, with smaller proportions in the research MRI group. In ageing populations, significant differences were observed in MRI metrics between research MRI and clinical MRI groups, and clinical health metric differences between research MRI, clinical MRI, and no-MRI groups. This questions whether research cohorts can adequately represent the greater ageing population undergoing imaging. These findings may also be useful to radiologists when interpreting neuroimaging of ageing.

Abstract WMP64: Late Lesion Growth Following Endovascular Therapy: Is 24 Hours Too Early to Assess Acute Infarct Size Including the Effects of Secondary Injury?

Background: Measurement of “final” lesion volume at 24hr following endovascular therapy (post-EVT) has been used in multiple studies as a surrogate for clinical outcome. However, despite successful recanalization, a significant proportion of patients do not experience favorable clinical outcome. Methods: This is a prospective study of acute ischemic stroke patients at two stroke centers who met the following criteria: i) anterior large vessel occlusion (LVO) acute ischemic stroke, ii) attempted EVT, iii) written informed consent obtained, and iv) had MRI post-EVT at 24hr and 5-day. We defined “Early” and “Late” lesion growth as ≥10mL lesion growth between baseline and 24hr DWI, and between 24hr DWI and 5-day FLAIR, respectively. Results: One hundred fourteen patients met study criteria with median age 67 years, 56% female, median admit NIHSS 19, 54% received IV or IA thrombolysis, 67% with M1 occlusion, and median baseline DWI volume 28.2mL. Successful recanalization was achieved in 86% and 67% had complete reperfusion, with an overall favorable clinical outcome rate of 54%. Nearly two thirds (65%) of the patients did not have Late lesion growth with a median volume change of -0.2mL between 24hr and 5-days and an associated high rate of favorable clinical outcome (65%). However, ~1/3 of patients (35%) did have significant Late lesion growth despite successful recanalization (85% TICI 2b/3). Late lesion growth patients had a 26.2mL change in Late lesion volume and 19.9mL change in Early lesion volume. These patients had an increased hemorrhagic transformation rate of 68% with only 1 in 3 patients having favorable clinical outcome. Late lesion growth was independently associated with incomplete reperfusion, hemorrhagic transformation, and unfavorable outcome even after adjusting for admit NIHSS and Early lesion growth. Conclusions: Approximately 1 out of 3 patients had Late lesion growth following EVT, with a favorable clinical outcome occurring in only 1 out of 3 of these patients. Identification of patients with Late lesion growth could be critical to guide clinical management and inform prognosis post-EVT. Additionally it can serve as an imaging biomarker for the development of adjunctive therapies to mitigate reperfusion injury.

Clinical and imaging predictors for hemorrhagic transformation of acute ischemic stroke after endovascular thrombectomy.

Hemorrhagic transformation (HT) is a common complication of endovascular thrombectomy (EVT) in patients with acute ischemic stroke (AIS). Our study aims to investigate the clinical and imaging predictors of HT and symptomatic intracranial hemorrhage (sICH) in patients who underwent EVT. A retrospective analysis of 118 patients undergoing EVT for acute anterior circulation stroke was performed. Potential clinical and imaging predictors of all patients were collected and multivariate logistic regression was performed. The risk prediction system was constructed according to the multivariate logistic regression results. The incidence of HT and sICH after EVT were 46.6% and 15.3%, respectively. The multivariate logistic regression results showed that Alberta Stroke Program Early CT Score (ASPECTS) (p = .001, odds ratio [OR] = 0.367, 95% [confidence interval] CI, 0.201-0.670), collateral status (p<.001, OR = 0.117, 95% CI, 0.042-0.325), relative cerebral blood flow (CBF) ratio (p = .025, OR = 0.943, 95% CI, 0.895-0.993), and blood glucose on admission (p = .012, OR = 1.258, 95% CI, 1.053-1.504) were associated with HT. While for sICH, collateral circulation (p = .007, OR = 0.148, 95% CI, 0.037-0.589), ASPECTS (p = .033, OR = 0.510, 95% CI, 0.274-0.946), and blood glucose (p = .005, OR = 1.304, 95% CI, 1.082-1.573) were independent factors. The predictive model for HT after EVT was established, and the sensitivity and specificity of it were 90.9% and 79.4%, respectively, with the area under the curve of 90.0% (84.5%-95.4%). Collateral status, ASPECTS, relative CBF ratio, and blood glucose on admission were predictors for HT in AIS patients, while collateral status, ASPECTS, and blood glucose on admission were also predictors for sICH. In addition, the established predictive model showed good diagnostic value for prediction of HT after EVT.

Update of Anticoagulation Use in Cardioembolic Stroke With a Special Reference to Endovascular Treatment.

Cardioembolic stroke is a major cause of morbidity, with a high risk of recurrence, and anticoagulation represents the mainstay of secondary stroke prevention in most patients. The implementation of endovascular treatment in routine clinical practice complicates the decision to initiate anticoagulation, especially in patients with early hemorrhagic transformation who are considered at higher risk of hematoma expansion. Late hemorrhagic transformation in the days and weeks following stroke remains a potentially serious complication for which we still do not have any established clinical or radiological prediction tools. The optimal time to initiate therapy is challenging to define since delaying effective secondary prevention treatment exposes patients to the risk of recurrent embolism. Consequently, there is clinical equipoise to define and individualize the optimal timepoint to initiate anticoagulation combining the lowest risk of hemorrhagic transformation and ischemic recurrence in cardioembolic stroke patients. In this narrative review, we will highlight and critically outline recent observational and randomized relevant evidence in different subtypes of cardioembolic stroke with a special focus on anticoagulation initiation following endovascular treatment. We will refer mainly to the commonest cause of cardioembolism, non-valvular atrial fibrillation, and examine the possible risk and benefit of anticoagulation before, during, and shortly after the acute phase of stroke. Other indications of anticoagulation after ischemic stroke will be briefly discussed. We provide a synthesis of available data to help clinicians individualize the timing of initiation of oral anticoagulation based on the presence and extent of hemorrhagic transformation as well as stroke severity.

Comparison of Characteristics and Outcomes Between Acute Ischemic Stroke Patients with Different Types of Heart Failure.

Acute ischemic stroke (AIS) can be complicated by heart failure involving preserved ejection fraction (HFpEF) or reduced ejection fraction (HFrEF), and whether or not the prognosis differs between the 2 types of patients remains unclear. We compared the clinical characteristics and outcomes of the 2 types of patients at 3 months after the stroke.We retrospectively analyzed patients who, between 1 January 2018 and 1 January 2021, experienced AIS that was complicated by HFrEF or HFpEF. All patients had been prospectively registered in the Chengdu Stroke Registry. Poor outcome was defined as a modified Rankin Scale (mRS) score of 2-6 at 3 months. Univariate and binary logistic regression was used to assess whether HFpEF was associated with a significantly worse prognosis than HFrEF.Among the final sample of 108 patients (60.2% men; mean age, 73.08 ± 10.82 years), 75 (69.4%) had HFpEF. Compared to HFrEF patients, those with HFpEF were older (P = 0.002), were more likely to have chronic kidney disease (P = 0.033), and were more likely to experience a poor outcome (P = 0.022). After adjustments, HFpEF was associated with significantly greater risk of poor outcome than HFrEF (OR 4.13, 95%CI 1.20-15.79, P = 0.029). However, rates of hemorrhagic transformation or mortality at 3 months after AIS did not differ significantly between the 2 types of heart failure (all P > 0.05).Patients with AIS involving HFpEF experience worse outcomes than those with HFrEF and therefore may require special monitoring and management. Our findings need to be verified in large prospective studies.

The benefit of favorable venous outflow profile is mediated through reduced microvascular dysfunction in acute ischemic stroke.

Venous outflow (VO) is emerging as a marker of microvascular integrity in acute ischemic stroke. Using hemorrhagic transformation (HT) and infarct growth as mediators, we tested whether a favorable VO profile benefited functional outcome by reducing consequences of microvascular dysfunction. Patients receiving thrombectomy in three comprehensive stroke centers due to acute anterior circulation occlusion were included. VO was assessed semi-quantitatively by the opacification of ipsilateral vein of Labbé, Trolard and superficial middle cerebral vein. HT was graded on follow-up CT. Infarct growth volume (IGV) was the difference of final infarct volume and baseline core volume. The association of VO and functional independence (90-day modified Rankin Scale ⩽ 2) was examined by logistic regression. Mediation analysis was performed among VO, HT or IGV, and functional outcome in patients with or without recanalization, respectively. In 242 patients analyzed, VO was strongly correlated with functional independence and VO ⩾ 4 was defined favorable. In 175 patients recanalized, favorable VO was associated with a reduced risk of HT (OR = 0.82, 95% CI 0.71-0.95, p = 0.008), which accounted for 13.1% of the association between VO and favorable outcome. In 67 patients without recanalization, favorable VO was associated with decreased IGV (β = -0.07, 95% CI -0.11 to -0.02, p = 0.007). The association of favorable VO and functional independence was no longer significant (aOR = 4.84, 95% CI 0.87-38.87, p = 0.089) after including IGV in the model, suggesting a complete mediation. In patients with acute anterior large vessel occlusion, the clinical benefit of VO may be mediated through reduced microvascular dysfunction.

Direct Exposure to Outdoor Air Pollution Worsens the Functional Status of Stroke Patients Treated with Mechanical Thrombectomy

Background The effect of air pollutants on the functional status of stroke patients in short-term follow-up is unknown. The aim of this study was to evaluate the effect of air pollution occurring in the stroke period and during hospitalization on the functional status of patients undergoing mechanical thrombectomy (MT). Methods Our study included stroke patients for which the individual-level exposure to ambient levels of O3, CO, SO2, NO2, PM2.5, and PM10 during the acute stroke period was assessed. The correlations between the air pollutants’ concentration and the patients’ functional state were analyzed. A total of 499 stroke patients (mean age: 70) were qualified. Results The CO concentration at day of stroke onset was found to be significant regarding the functional state of patients on the 10th day (OR 0.014 95% CI 0–0.908, p = 0.048). The parameters which increased the risk of death in the first 10 days were as follows: NIHSS (OR 1.27; 95% CI 1.15–1.42; p &lt; 0.001), intracranial bleeding (OR 4.08; 95% CI 1.75–9.76; p = 0.001), and SO2 concentration on day 2 (OR 1.21; 95% CI 1.02–1.47; p = 0.03). The parameters which increased the mortality rate within 90 days include age (OR 1.07; 95% CI 1.02–1.13; p = 0.005) and NIHSS (OR 1.37; 95% CI 1.19–1.63; p &lt; 0.001). Conclusions Exposure to air pollution with CO and SO2 during the acute stroke phase has adverse effects on the patients’ functional status. A combination of parameters, such as neurological state, hemorrhagic transformation, and SO2 exposure, is unfavorable in terms of the risk of death during a hospitalization due to stroke. The risk of a worsened functional status of patients in the first month of stroke rises along with the increase in particulate matter concentrations within the first days of stroke.

Early apixaban administration considering the size of infarction and functional outcome in acute ischemic stroke.

Atrial fibrillation-related stroke (AF-stroke) is associated with an adverse prognosis, characterized by a high incidence of progression, recurrence, and hemorrhagic transformation. Our study aims to investigate the potential benefits of stratified early administration of apixaban, taking into account infarct size during the acute phase, in order to enhance functional outcomes. We conducted this study at a tertiary referral stroke center, enrolling acute AF-stroke patients who received apixaban during the acute phase. Infarct size was categorized as small, medium, or large based on diffusion-weighted imaging. Patients were divided into two groups: standard initiation (apixaban initiation based on guidelines, i.e., small: 4 days, medium: 7 days, large: 14 days after stroke) and early initiation (initiation before guideline recommendations) groups. We compared favorable outcomes (modified Rankin scale score ≤ 2) at 3 months post-stroke, stroke progression, early recurrence, and symptomatic hemorrhagic transformation (sHT) between the groups. Out of 299 AF-stroke patients, 170 (56.9%) were in the early initiation group. A favorable outcome was observed in 105 (61.8%) patients in the early initiation group and 62 (48.1%) patients in the standard initiation group (p = 0.019). Stroke progression or early recurrence occurred less frequently in the early initiation group (4.7% versus 13.2%, p = 0.007). Nevertheless, no difference in sHT was noted between the groups. Early initiation of apixaban was independently associated with favorable outcomes (odds ratio: 2.75, 95% confidence interval: 1.44-5.28, p = 0.002). Our findings suggest that early initiation of apixaban, tailored to infarct size, could serve as a viable strategy to enhance functional outcomes. This approach may potentially decrease stroke progression and early recurrence without elevating the risk of sHT.

Safety and efficacy of platelet glycoprotein VI inhibition in acute ischaemic stroke (ACTIMIS): a randomised, double-blind, placebo-controlled, phase 1b/2a trial

Antagonists of glycoprotein VI-triggered platelet activation used in combination with recanalisation therapies are a promising therapeutic approach in acute ischaemic stroke. Glenzocimab is an antibody fragment that inhibits the action of platelet glycoprotein VI. We aimed to determine and assess the safety and efficacy of the optimal dose of glenzocimab in patients with acute ischaemic stroke eligible to receive alteplase with or without mechanical thrombectomy. This randomised, double-blind, placebo-controlled study with dose-escalation (1b) and dose-confirmation (2a) phases (ACTIMIS) was done in 26 stroke centres in six European countries. Participants were adults (≥18 years) with disabling acute ischaemic stroke with a National Institutes of Health Stroke Scale score of 6 or higher before alteplase administration. Patients were randomly assigned treatment using a central electronic procedure. Total administered dose at the end of the intravenous administration was 125 mg, 250 mg, 500 mg, and 1000 mg of glenzocimab or placebo in phase 1b and 1000 mg of glenzocimab or placebo in phase 2a. Treatment was initiated 4·5 h or earlier from stroke symptom onset in patients treated with alteplase with or without mechanical thrombectomy. The sponsor, study investigator and study staff, patients, and central laboratories were all masked to study treatment until database lock. Primary endpoints across both phases were safety, mortality, and intracranial haemorrhage (symptomatic, total, and fatal), assessed in all patients who received at least a partial dose of study medication (safety set). The trial is registered on ClinicalTrials.gov, NCT03803007, and is complete. Between March 6, 2019, and June 27, 2021, 60 recruited patients were randomly assigned to 125 mg, 250 mg, 500 mg, or 1000 mg glenzocimab, or to placebo in phase 1b (n=12 per group) and were included in the safety analysis. Glenzocimab 1000 mg was well tolerated and selected as the phase 2a recommended dose; from Oct 2, 2020, to June 27, 2021, 106 patients were randomly assigned to glenzocimab 1000 mg (n=53) or placebo (n=53). One patient in the placebo group received glenzocimab in error and therefore 54 and 52, respectively, were included in the safety set. In phase 2a, the most frequent treatment-emergent adverse event was non-symptomatic haemorrhagic transformation, which occurred in 17 (31%) of 54 patients treated with glenzocimab and 26 (50%) of 52 patients treated with placebo. Symptomatic intracranial haemorrhage occurred in no patients treated with glenzocimab compared with five (10%) patients in the placebo group. All-cause deaths were lower with glenzocimab 1000 mg (four [7%] patients) than with placebo (11 [21%] patients). Glenzocimab 1000 mg in addition to alteplase, with or without mechanical thrombectomy, was well tolerated, and might reduce serious adverse events, intracranial haemorrhage, and mortality. These findings support the need for future research into the potential therapeutic inhibition of glycoprotein VI with glenzocimab plus alteplase in patients with acute ischaemic stroke. Acticor Biotech.

Dysautonomia and activity in the early stroke recovery period.

Maintaining cerebral perfusion in the early stages of recovery after stroke is paramount. Autoregulatory function may be impaired during this period leaving cerebral perfusion directly reliant on intravascular volume and blood pressure (BP) with increased risk for expanding cerebral infarction during periods of low BP and hemorrhagic transformation during BP elevations. We suspected that dysautonomia is common during the acute period related to both pre-existing vascular risk factors and potentially independent of such conditions. Thus, we sought to understand the state of the science specific to dysautonomia and acute stroke. The scoping review search included multiple databases and key terms related to acute stroke and dysautonomia. The team employed a rigorous review process to identify, evaluate, and summarize relevant literature. We additionally summarized common clinical approaches used to detect dysautonomia at the bedside. The purpose of this scoping review is to understand the state of the science for the identification, treatment, and impact of dysautonomia on acute stroke patient outcomes. There is a high prevalence of dysautonomia among persons with stroke, though there is significant variability in the type of measures and definitions used to diagnose dysautonomia. While dysautonomia appears to be associated with poor functional outcome and post-stroke complications, there is a paucity of high-quality evidence, and generalizability is limited by heterogenous approaches to these studies. There is a need to establish common definitions, standard measurement tools, and a roadmap for incorporating these measures into clinical practice so that larger studies can be conducted.

Improving stroke outcomes in hyperglycemic mice by modulating tPA/NMDAR signaling to reduce inflammation and hemorrhages

AbstractThe pharmacological intervention for ischemic stroke hinges on intravenous administration of the recombinant tissue-type plasminogen activator (rtPA, Alteplase/Actilyse) either as a standalone treatment or in conjunction with thrombectomy. However, despite its clinical significance, broader use of rtPA is constrained because of the risk of hemorrhagic transformations (HTs). Furthermore, the presence of diabetes or chronic hyperglycemia is associated with an elevated risk of HT subsequent to thrombolysis. This detrimental impact of tPA on the neurovascular unit in patients with hyperglycemia has been ascribed to its capacity to induce endothelial N-methyl-D-aspartate receptor (NMDAR) signaling, contributing to compromised blood-brain barrier integrity and neuroinflammatory processes. In a mouse model of thromboembolic stroke with chronic hyperglycemia, we assessed the effectiveness of rtPA and N-acetylcysteine (NAC) as thrombolytic agents. We also tested the effect of blocking tPA/NMDAR signaling using a monoclonal antibody, Glunomab. Magnetic resonance imaging, speckle contrast imaging, flow cytometry, and behavioral tasks were used to evaluate stroke outcomes. In hyperglycemic animals, treatment with rtPA resulted in lower recanalization rates and increased HTs. Conversely, NAC treatment reduced lesion sizes while mitigating HTs. After a single administration, either in standalone or combined with rtPA-induced thrombolysis, Glunomab reduced brain lesion volumes, HTs, and neuroinflammation after stroke, translating into improved neurological outcomes. Additionally, we demonstrated the therapeutic efficacy of Glunomab in combination with NAC or as a standalone strategy in chronic hyperglycemic animals. Counteracting tPA-dependent endothelial NMDAR signaling limits ischemic damages induced by both endogenous and exogenous tPA, including HTs and inflammatory processes after ischemic stroke in hyperglycemic animals.

Heterogeneous treatment effects of Cerebrolysin as an early add-on to reperfusion therapy: post hoc analysis of the CEREHETIS trial.

Background: There has been intensive research into enhancing the effects of reperfusion therapy to mitigate hemorrhagic transformation (HT) in stroke patients. Using neuroprotective agents alongside intravenous thrombolysis (IVT) appears a promising approach. Cerebrolysin is one of the candidates since it consists of neuropeptides mimicking the action of neurotrophic factors on brain protection and repair. Objectives: We looked at treatment effects of Cerebrolysin as an early add-on to IVT in stroke patients with varying HT risk. Methods: It was post hoc analysis of the CEREHETIS trial (ISRCTN87656744). Patients with middle cerebral artery infarction (n = 238) were selected from the intention-to-treat population. To stratify participants according to their HT risk, the DRAGON, SEDAN and HTI scores were computed for each eligible subject using on-admission data. The study endpoints were any and symptomatic HT, and functional outcome measured with the modified Rankin Scale (mRS) on day 90. Favorable functional outcome (FFO) was defined as an mRS ≤2. The performance of each stratification tool was estimated with regression approaches. Heterogeneous treatment effect analysis was conducted using techniques of meta-analysis and the matching-smoothing method. Results: The HTI score outperformed other tools in terms of HT risk stratification. Heterogeneity of Cerebrolysin treatment effects was moderate (I2, 35.8%-56.7%; H2, 1.56-2.31) and mild (I2, 10.9%; H2, 1.12) for symptomatic and any HT, respectively. A significant positive impact of Cerebrolysin on HT and functional outcome was observed in the moderate (HTI = 1) and high (HTI ≥2) HT risk patients, but it was neutral in those with the low (HTI = 0) risk. In particular, there was a steady decline in the rate of symptomatic (HTI = 0 vs. HTI = 4: by 4.3%, p = 0.077 vs. 21.1%, p < 0.001) and any HT (HTI = 0 vs. HTI = 4: by 1.2%, p = 0.737 vs. 32.7%, p < 0.001). Likewise, an mRS score reduction (HTI = 0 vs. HTI = 4: by 1.8%, p = 0.903 vs. 126%, p < 0.001) with a reciprocal increase of the fraction of FFO patients (HTI = 0 vs. HTI = 4: by 1.2% p = 0.757 vs. 35.5%, p < 0.001) was found. Conclusion: Clinically meaningful heterogeneity of Cerebrolysin treatment effects on HT and functional outcome was established in stroke patients. The beneficial effects were significant in those whose estimated on-admission HT risk was either moderate or high.

Thrombolytic therapy based on lyophilized platelet-derived nanocarriers for ischemic stroke

BackgroundIntravenous administration of fibrinolytic drugs, such as recombinant tissue plasminogen activator (rtPA) is the standard treatment of acute thrombotic diseases. However, current fibrinolytics exhibit limited clinical efficacy because of their short plasma half-lives and risk of hemorrhagic transformations. Platelet membrane-based nanocarriers have received increasing attention for ischemic stroke therapies, as they have natural thrombus-targeting activity, can prolong half-life of the fibrinolytic therapy, and reduce side effects. In this study we have gone further in developing platelet-derived nanocarriers (defined as cellsomes) to encapsulate and protect rtPA from degradation. Following lyophilization and characterization, their formulation properties, biocompatibility, therapeutic effect, and risk of hemorrhages were later investigated in a thromboembolic model of stroke in mice.ResultsCellsomes of 200 nm size and loaded with rtPA were generated from membrane fragments of human platelets. The lyophilization process did not influence the nanocarrier size distribution, morphology, and colloidal stability conferring particle preservation and long-term storage. Encapsulated rtPA in cellsomes and administered as a single bolus showed to be as effective as a continuous clinical perfusion of free rtPA at equal concentration, without increasing the risk of hemorrhagic transformations or provoking an inflammatory response.ConclusionsThis study provides evidence for the safe and effective use of lyophilized biomimetic platelet-derived nanomedicine for precise thrombolytic treatment of acute ischemic stroke. In addition, this new nanoformulation could simplify the clinical use of rtPA as a single bolus, being easier and less time-consuming in an emergency setting than a treatment perfusion, particularly in stroke patients. We have successfully addressed one of the main barriers to drug application and commercialization, the long-term storage of nanomedicines, overcoming the potential chemical and physical instabilities of nanomedicines when stored in an aqueous buffer.

The differences of fibrinogen levels in various types of hemorrhagic transformations.

Hemorrhagic transformation (HT) is a serious complication that can occur spontaneously after an acute ischemic stroke (AIS) or after a thrombolytic/mechanical thrombectomy. Our study aims to explore the potential correlations between fibrinogen levels and the occurrence of spontaneous HT (sHT) and HT after mechanical thrombectomy (tHT). A total of 423 consecutive AIS patients diagnosed HT who did not undergone thrombolysis and 423 age- and sex-matched patients without HT (non-HT) were enrolled. Fibrinogen levels were measured within 24 h of admission after stroke. The cohorts were trisected according to fibrinogen levels. The HT were further categorized into hemorrhagic infarction (HI) or parenchymal hematoma (PH) based on their imaging characteristics. In sHT cohort, fibrinogen levels were higher in HT patients than non-HT patients (p < 0.001 versus p = 0.002). High fibrinogen levels were associated with the severity of HT. HT patients without atrial fibrillation (AF) had higher levels of fibrinogen compared to non-HT (median 3.805 vs. 3.160, p < 0.001). This relationship did not differ among AF patients. In tHT cohort, fibrinogen levels were lower in HT patients than non-HT patients (p = 0.002). Lower fibrinogen levels were associated with the severity of HT (p = 0.004). The highest trisection of fibrinogen both in two cohorts were associated with HT [sHT cohort: OR = 2.515 (1.339-4.725), p = 0.016; that cohort: OR = 0.238 (0.108-0.523), p = 0.003]. Our study suggests that lower fibrinogen level in sHT without AF and higher fibrinogen level in tHT are associated with more severe HT.