Intracranial Hemorrhage Research Articles

Anti-Inflammatory Thrombolytic JX10 (TMS-007) in Late Presentation of Acute Ischemic Stroke.

Contemporary thrombolytics in acute ischemic stroke are limited to administration within 4.5 hours of last known normal. JX10 (formerly TMS-007), a Stachybotrys microspora triprenyl phenol family member, may extend this therapeutic window. In this multicenter, randomized, double-blind, placebo-controlled, dose-escalation phase 2a study, JX10 or placebo was administered as a single intravenous infusion to Japanese patients with acute ischemic stroke who were unable to receive tissue-plasminogen activator or thrombectomy within 12 hours of last known normal. Primary end point was incidence of symptomatic intracranial hemorrhage with a worsening National Institutes of Health Stroke Scale score of ≥4 points within 24 hours of drug administration (symptomatic intracranial hemorrhage incidence). Ninety patients received either placebo (n=38; female 26.3%) or JX10 at 1, 3, or 6 mg/kg (n=6, 18, 28; female 0%, 33.3%, and 42.9%, respectively). Median age (range) and baseline median (range) National Institutes of Health Stroke Scale scores were respectively 76.5 (42-87) and 8 (6-21) for the combined JX10 cohort (JX10 Cohorts) and 75.0 (34-85) and 8 (6-22) for placebo. Median (range) dosing time since last known normal was 9.5 (5.0-12.1) and 10.0 (3.7-12.0) hours for JX10 Cohorts and placebo, respectively. Symptomatic intracranial hemorrhage incidence was 0% (0/52 [95% CI, 0.0-5.6]) for JX10 Cohorts versus 2.6% (1/38 [95% CI, 0.1-13.8]) for placebo (P=0.42). Vessel patency at 24 hours (secondary end point) in patients with baseline arterial occlusive lesion score <3 (39/90) improved in 58.3% (14/24) of patients in JX10 Cohorts versus 26.7% (4/15) for placebo (odds ratio, 4.23 [95% CI, 0.99-18.07]). In JX10 Cohorts, a significantly higher proportion of patients had modified Rankin Scale scores of 0 to 1 on day 90 (secondary end point) versus placebo (JX10: 21/52, 40.4% versus placebo: 7/38, 18.4%; P=0.03). JX10 was well tolerated and may expand the acute ischemic stroke therapeutic window as a novel thrombolytic agent. URL: https://rctportal.niph.go.jp/en; Unique identifier: jRCT2080223786.

Endovascular Treatment of Patients With Acute Ischemic Stroke With Tandem Lesions Presenting With Low Alberta Stroke Program Early Computed Tomography Score.

Recent trials confirmed the efficacy and safety of endovascular thrombectomy in patients with low Alberta Stroke Program Early Computed Tomography Score (ASPECTS); however, evidence in tandem lesions is limited. This study evaluates endovascular thrombectomy safety and efficacy in patients with acute large-vessel occlusion with tandem lesions, stratified by baseline ASPECTS. We conducted a retrospective analysis of data from 16 centers. Inclusion criteria included the following: age ≥18 years, anterior circulation tandem lesions, endovascular thrombectomy <24 hours of symptom onset, and ≥70% internal carotid artery stenosis/occlusion. Patients were categorized into low (0-5) and high (6-10) ASPECTS. Inverse probability of treatment weighting matching was used to balance the groups. Primary outcomes included the following: 90-day modified Rankin Scale (mRS) score 0 to 2 and symptomatic intracranial hemorrhage. Secondary outcomes included the following: ordinal mRS, mRS 0 to 3, modified Thrombolysis in Cerebral Infarction ≥2b and 2c-3, petechial hemorrhage, parenchymal hematoma (1/2), early neurologic improvement, and mortality. Of 691 patients, 44 had ASPECTS 0 to 5 and 505 had ASPECTS 6 to 10. Patients with low ASPECTS had lower odds of 90-day mRS 0 to 2 (adjusted odds ratio [OR], 0.48; P=0.036) and higher odds of symptomatic intracranial hemorrhage (adjusted OR, 3.78; P=0.014). Additional significant differences were found in mRS shift, mRS 0 to 3, parenchymal hematoma 2, and mortality. In interaction analysis, the association between low ASPECTS and functional outcome persisted only in the internal carotid artery occlusion subgroup, with no significant interaction indicating no reason to suppose a difference between the effect of both subgroups. Endovascular thrombectomy in patients with tandem lesions with low ASPECTS is associated with reduced odds of functional recovery and increased symptomatic intracranial hemorrhage risk, when compared with patients with high ASPECTS. However, 30% of patients with low ASPECTS achieved 90-day functional independence, suggesting potential benefit for a nonnegligible proportion of patients.

Systematic vitamin K antagonist reversal with prothrombin complex concentrate in patients with mild traumatic brain injury: randomized controlled trial

Background and importance Traumatic brain injury (TBI) in patients on vitamin K antagonists (VKAs) is linked to a high rate of intracranial hemorrhage (ICH). Rapid reversal can reduce ICH progression and mortality, but its effectiveness depends on the time between bleeding onset and coagulation normalization. Objective The PREVACT study aimed to assess the efficacy and safety of prompt systematic reversal of anticoagulation in patients presenting to emergency departments (EDs) for recent mild-TBI while receiving a VKA. Intervention A randomized, open-label, blinded-endpoint clinical trial was conducted in 21 French EDs. Patients receiving a VKA, having experienced a TBI within the last 6 h, and presenting a Glasgow Coma Score ≥13 were included. Patients were randomized to systematic immediate VKA reversal with 25 IU/kg of four-factor prothrombin complex concentrate (4f-PCC) before any investigation (intervention group) or standard-of-care signifying reversal only if the initial cranial computed tomography (CT) scan indicated ICH (control group). The primary outcome was the rate of ICH detected on a cranial CT scan 24 h post-inclusion. Results The study was prematurely stopped for logistic reasons after the randomization of 202 patients (101 and 101 in the intervention and control groups, respectively, mean age 90; 51.8% female). On the 24-h cranial CT scan, 6 of 98 patients (6.1%) in the intervention group manifested ICH vs. 12 of 99 patients (12.1%) in the control group [odds ratio: 0.47 (95% confidence interval: 0.14–1.44); P = 0.215]. Conclusion In patients with recent mild-TBI receiving a VKA, systematic prompt reversal with 4f-PCC did not statistically significantly reduce ICH rate at 24 h. However, the study was prematurely stopped and does not exclude a clinically relevant benefit of the strategy tested. Trial registration Clinicaltrials.gov (NCT01961804).

Neonatal Presentation of Severe Hemophilia A: An Original Case Report and a Literature Review

Introduction: We report the case of a neonate diagnosed with severe hemophilia A (HA) and conduct a literature review of cases of severe HA presenting at the neonatal age to help define the clinical diagnostic findings and existing differences between the sporadic and familial onset of this condition. Report of a Case: A 6-day-old newborn presented with worsening pallor, inappetence, and hyporeactivity for 48 h. The diagnosis was severe hemophilia A (HA), leading to an unfavorable outcome. A literature review focusing on case reports and series focusing on the clinical expression of HA in neonates was conducted, documenting clinical presentation, family history, and outcomes. Literature review: Forty patients were included. HA was observed in five cases (12.5%) of very preterm births (≤32 weeks) and in four cases (10%) of moderately or late preterm births. Seventeen patients (43%) had a family history, with inheritance being sporadic (21 newborns, 53%) or acquired (2 cases, 4%). Clinical onset typically occurred within the first week of life (approximately 8 out of 10 cases), while only three cases (7.5%) had onset after the first month. Inherited cases presented with hemorrhagic states (nine cases), hypovolemic shock (five cases), or intracranial hypertension (two cases). Sporadic cases showed localized bleeding (11 cases), hypovolemic shock (5 cases), or neurological symptoms like seizures and anisocoria (5 cases). Acquired cases included severe intracranial hemorrhage in one case. Conclusions: Neonatal HA can manifest with severe symptoms and rapid progression, making early diagnosis crucial. Non-specific signs and the absence of coagulophaty disorders in family history can delay diagnosis. Symptoms like prolonged bleeding, cutaneous hematomas, or intracranial bleeding necessitate ruling out major coagulopathy, and neurological signs require immediate imaging to exclude intracranial bleeding.

High mechanical thrombectomy procedural volume is not a reliable predictor of improved thrombectomy outcomes in patients with acute ischemic stroke in the United States.

The volume of mechanical thrombectomy (MT) performed at hospitals is used as one of the criteria for advanced-level designation for stroke care. Our study sought to determine the relationship between annual MT procedural volume and in-hospital outcomes in acute ischemic stroke patients undergoing MT in the United States. We analyzed the National Inpatient Sample from 2016 to 2020. The hospitals were grouped into quartiles based on the volume of MT procedures performed within the calendar year. We compared the rates of routine discharge/home health care; in-hospital mortality, and post-treatment intracranial hemorrhage (ICH) between the quartiles after adjusting for potential confounders. Patients undergoing MT ranged from 15,395 in quartile 1 to 78,510 MT in quartile 4. There were lower rates of discharge home/self-care of 22.5%, 20.8%, and 20.8% for quartiles 2, 3, and 4, respectively, compared with 34.9% in quartile 1. The odds of ICH increased to 1.81 (p < 0.001), 1.84 (p < 0.001), and 1.98 (p < 0.001) among the quartiles from lowest to highest procedural volumes. The odds of home discharge/self-care decreased to 0.66 (p < 0.001), 0.60 (p < 0.001), and 0.63 (p < 0.001) among the quartiles from lowest to highest procedural volumes. The odds of in-hospital mortality increased to 1.92 (p < 0.001), 1.99 (p < 0.001), and 1.84 (p < 0.001) among the quartiles from lowest to highest procedural volumes. We observed a paradoxical relationship between adverse outcomes and the annual procedural volume of MT at the hospital presumably due to the higher severity of acute ischemic stroke treated at high-volume hospitals.

A Case Report of a Suspected Neonatal Alloimmune Thrombocytopenia in a Tertiary Health Institution

Fetal and neonatal alloimmune thrombocytopenia FNAIT is the leading cause of severe thrombocytopenia in the fetus and neonate leading to serious bleeding, intracranial haemorrhage and death and also intracranial haemorrhage in full-term infants. We reported a case of a 33-year-old woman who was delivered of a male neonate via Emergency lower segment Cesarean section CS on account of premature rupture of the membrane with oligo hydramnios at an estimated gestational age EGA of 29 weeks 3 days. Her blood group is O Rhesus D positive, and Genotype HbAA. No known premorbid illness. Her last confinement was of a male child delivered via CS and died within 12 hours of birth. This reported case of suspected FNAIT was a baby received alive after CS with birthweight of 1,060g and APGAR score of 7185 transiently, and was noticed to be bleeding from the mouth and anus shortly after birth. Thereafter, he had thrombocytopenia, persistent anaemia, several apneic attacks, seizures, desaturation and died after 42 hours of life despite all prompt clinical interventions. Autopsy summary includes anaemia, central cyanosis, petechial hemorrhage, diffuse alveolar damage, cerebral edema, acute tubular necrosis, small for gestational age and placental vasculopathy. Conclusion: Fetal and neonatal alloimmune thrombocytopenia is a rare disorder and yet poses a challenging diagnosis and treatment plan in resource-limited centres especially in developing countries. Although the clinical findings of the reported suspected case were not classical as previously reported by other studies, they’re pointers to our curiosity and open to further criticism.

Long-term hypoxia modulates depolarization activation of BKCa currents in fetal sheep middle cerebral arterial myocytes

IntroductionPrevious evidence indicates that gestational hypoxia disrupts cerebrovascular development, increasing the risk of intracranial hemorrhage and stroke in the newborn. Due to the role of cytosolic Ca2+ in regulating vascular smooth muscle (VSM) tone and fetal cerebrovascular blood flow, understanding Ca2+ signals can offer insight into the pathophysiological disruptions taking place in hypoxia-related perinatal cerebrovascular disease. This study aimed to determine the extent to which gestational hypoxia disrupts local Ca2+ sparks and whole-cell Ca2+ signals and coupling with BKCa channel activity.MethodsConfocal imaging of cytosolic Ca2+ and recording BKCa currents of fetal sheep middle cerebral arterial (MCA) myocytes was performed. MCAs were isolated from term fetal sheep (∼140 days of gestation) from ewes held at low- (700 m) and high-altitude (3,801 m) hypoxia (LTH) for 100+ days of gestation. Arteries were depolarized with 30 mM KCl (30K), in the presence or absence of 10 μM ryanodine (Ry), to block RyR mediated Ca2+ release.ResultsMembrane depolarization increased Ry-sensitive Ca2+ spark frequency in normoxic and LTH groups along with BKCa activity. LTH reduced Ca2+ spark and whole-cell Ca2+ activity and induced a large leftward shift in the voltage-dependence of BKCa current activation. The influence of LTH on the spatial and temporal aspects of Ca2+ sparks and whole-cell Ca2+ responses varied.DiscussionOverall, LTH attenuates Ca2+ signaling while increasing the coupling of Ca2+ sparks to BKCa activity; a process that potentially helps maintain oxygen delivery to the developing brain.

Brainstem hemorrhage associated with venous hypertensive myelopathy without dural arteriovenous fistula: illustrative case.

Venous hypertensive myelopathy (VHM), formerly known as "Foix-Alajouanine syndrome," is a spinal cord dysfunction caused by impaired perfusion of the spinal cord. Most cases are attributed to spinal dural arteriovenous fistulas (dAVFs), but there are scattered reports of VHM without concomitant dAVF. Furthermore, no cases of VHM associated with intracranial hemorrhage exist. A 68-year-old man with a history of hypertension presented with a sudden headache, proximal paresis of the left upper extremity, impaired pain and temperature sensation in the right upper extremity, dysphagia, and dysarthria. Computed tomography scans showed intraparenchymal hemorrhage in the left medulla oblongata and a linear, continuous high-density area extending from the medulla oblongata to the cervical spinal cord. Magnetic resonance images showed cervical spondylosis at the C5-6 and C6-7 levels, with high signal intensity changes from the medulla oblongata to the lower cervical cord on T2-weighted images. Cerebral angiography showed no abnormal vessels. Conservative treatment gradually improved symptoms and the high signal intensity areas. This case highlights intracranial hemorrhage occurring from extracranial causes and the possibility of VHM due to cervical spondylosis. When hemorrhagic lesions of the craniovertebral junction or spinal parenchymal lesions are encountered, the underlying pathology should be investigated thoroughly and systematically. https://thejns.org/doi/10.3171/CASE24441.

Bleeding Associated With Antiarrhythmic Drugs in Patients With Atrial Fibrillation Using Direct Oral Anticoagulants: A Nationwide Population Cohort Study.

This study investigated drug-drug interactions in patients with atrial fibrillation taking both a direct oral anticoagulant (DOAC) and an antiarrhythmic drug. Using data from the National Health Insurance database (2012-2018), we identified 78 805 patients with atrial fibrillation on DOACs, with 24 142 taking amiodarone, 8631 taking propafenone, 2784 taking dronedarone, 297 taking flecainide, 177 taking sotalol, and 42 772 on DOACs alone. Patients with bradycardia, heart block, heart failure, mitral stenosis, prosthetic valves, or incomplete data were excluded. Propensity score matching compared those taking both DOACs and antiarrhythmic drugs with those on DOACs alone. There was an increased risk of major bleeding in patients concomitantly taking DOACs with amiodarone when compared with matched patients taking DOACs alone (hazard ratio [HR],1.13 [95% CI, 1.04-1.23]; P=0.0044), particularly in patients taking dabigatran (HR, 1.19 [95% CI, 1.03-1.38]; P=0.0175). No significant difference in bleeding risk was found for propafenone, dronedarone, flecainide, or sotalol. The small sample sizes in the flecainide and sotalol groups limit interpretation. Notably, intracranial bleeding risk was higher in patients on DOACs and amiodarone, regardless of age. Additionally, patients <80 years old taking dabigatran with amiodarone or propafenone had a higher risk of gastrointestinal bleeding. Concomitant use of DOACs with amiodarone, but not dronedarone or propafenone, increases the risk of major bleeding, particularly intracranial bleeding. This study provides new evidence to guide clinicians to tailor concomitant anticoagulation and antiarrhythmic therapy for patients with atrial fibrillation.

Medial intracranial carotid artery calcifications and hematoma expansion in deep intracerebral hemorrhage.

Medial intracranial carotid artery calcifications (ICAC) are associated with impaired vascular physiology, increased arterial stiffness and pulse pressure. Their presence might therefore be associated with increased risk of intracerebral hemorrhage (ICH) expansion, according to the avalanche model. We explored the association between ICAC presence and pattern and hematoma expansion (HE). Retrospective analysis of a monocentric, prospectively collected cohort of ICH patients admitted between June 2017 and October 2023. ICAC pattern was determined by Kockelkoren's rating scale on admission CT; medial ICAC were defined with a >6 points cutoff. A follow-up CT scan was performed within 72 h. HE was analyzed as a dichotomous (≥6 mL and/or ≥33%) and as a categorical (none/mild/moderate/severe) variable, and its predictors were explored with logistic and ordinal regression respectively, accounting for baseline volume, onset-to-CT time, and anticoagulation. All the analyses were stratified by ICH location (supratentorial deep vs lobar ICH). A total of 201 patients were included (median age 78, 42% females, 59% deep ICH). Medial ICAC were significantly more common in deep ICH with HE compared with non-expanders (72% vs 49%, p = 0.03), whereas there was no association between ICAC and HE in lobar ICH (53% vs 52%, p = 0.85). This association between medial ICAC and HE in deep ICH remained significant in logistic (aOR 3.11, 95% CI [1.19-9.06], p = 0.03) and ordinal regression (acOR 2.42, 95% CI [1.19-4.99], p = 0.01). Ipsilateral medial ICAC are associated with higher odds of HE in deep ICH. Our findings are best interpreted as hypothesis generating, requiring prospective validation and further research to characterize the underlying biological mechanisms.

Development and Validation of a Novel Classification System and Prognostic Model for Open Traumatic Brain Injury: A Multicenter Retrospective Study.

Open traumatic brain injury (OTBI) is associated with high mortality and morbidity; however, the classification of these injuries and the determination of patient prognosis remain uncertain, hindering the selection of optimal treatment strategies. This study aimed to develop and validate a novel OTBI classification system and a prognostic model for poor prognosis. This retrospective study included patients with isolated OTBI who received treatment at three large medical centersin China between January 2020 and June 2022 as the training set. Data on patients with OTBI collected at the Fuzong Clinical Medical College of Fujian Medical University between July 2022 and June 2023 were used as the validation set. Clinical parameters, including clinical data at admission, radiological and laboratory findings, details of surgical methods, and prognosis were collected. Prognosis was assessed through a dichotomized Glasgow Outcome Scale (GOS). A novel OTBI classification was proposed, categorizing patients based on a combination of intracranial hematoma and midline shift observed on imaging, and logistic regression analyses were performed to identify risk factors associated with poor prognosis and to investigate the association between the novel OTBI classification and prognosis. Finally, a nomogram suitable for clinical application was established and validated. Multivariable logistic regression analysis identified OTBI classification type C (p<0.001), a Glasgow Coma Scale score (GCS)≤8 (p<0.001), subarachnoid hemorrhage (SAH) (p=0.004), subdural hematoma (SDH) (p=0.011), and coagulopathy (p=0.020) as independent risk factors for poor prognosis. The addition of the OTBI classification to a model containing all the other identified prognostic factors improved the predictive ability of the model (Z=1.983; p=0.047). In the validation set, the model achieved an area under the curve (AUC) of 0.917 [95% confidence interval (CI)=0.864-0.970]. The calibration curve closely approximated the ideal curve, indicating strong predictive performance of the model. The implementation of our proposed OTBI classification system and its use alongside the other prognostic factors identified here may improve the prediction of patient prognosis and aid in the selection of the most suitable treatment strategies.

Comparing validated stroke screening scales for identifying large and medium vessel occlusions: a prospective observational cohort study.

Rapid prehospital identification of acute ischemic stroke secondary to large vessel occlusions (AIS-LVO) has been successful in triaging patients, but the use of stroke screening scales often varies. This study aims to compare different stroke screening scales for the detection of anterior and posterior circulation AIS-LVO and AIS secondary to medium vessel occlusions (AIS-MeVO). We prospectively analyzed stroke alert activations at a comprehensive stroke center between August 1, 2022 and December 31, 2023. We applied eight stroke screening scales (BE-FAST, LAMS, PASS, FAST-ED, EMS RACE, 3-ISS, VAN, and NIHSS) to each stroke alert in the emergency department (ED) and inpatient wards. The final diagnosis was classified as AIS-LVO or AIS-MeVO, AIS without LVO or MeVO, intracranial hemorrhage, transient ischemic attack, or stroke mimic. A total of 198 patients were analyzed. The mean age was 63.9±15.3 years, 62.1% were female (n=123), and 84.3% were African American/black subjects (n=167). The LAMS scale had a strong performance (area under the curve (AUC) 0.750 (95% CI 0.668 to 0.831)), closely followed by the FAST-ED (AUC 0.736 (95% CI 0.649 to 0.822)) and the VAN (AUC 0.735 (95% CI 0.651 to 0.818)) scales. Cut-off points selected from coordinates of the receiver operating characteristic curves were 3, 3, and a positive VAN, respectively. This is the first prospective cohort study to compare the performance of eight different screening scales among stroke alerts for detection of AIS-LVO and AIS-MeVO. We found LAMS to be the most discriminative tool, followed by FAST-ED and VAN. However, the findings were non-significant, reinforcing existing retrospective literature that these validated screening scales perform similarly and one is not superior.

Single-Center Experience With Endovascular Therapy in Acute Occlusion of ICAS: Preferred Stent Thrombectomy Versus Preferred Angioplasty.

The preferred endovascular therapy (EVT) for large-vessel occlusion in intracranial atherosclerosis (ICAS) is unknown. We compared the efficacy of preferred stent thrombectomy and preferred angioplasty in patients with acute large-vessel occlusion in ICAS. Data from consecutive EVT patients (May 2020 to September 2023) with acute middle cerebral artery occlusion in ICAS were retrospectively analyzed. Preferred angioplasty was performed if there was a preoperative "microcatheter first-pass effect;" otherwise, preferred stent thrombectomy was performed. Analyses were grouped according to the two EVT treatments. Clinical data of all patients, including the time from puncture to recanalization, rate of successful reperfusion, early neurological improvement, intracranial hemorrhage, and modified Rankin Scale score at 90 days, were recorded and analyzed. Six-two patients were enrolled in this study (mean age was 60.66±13.21y, 22.6% female). The preferred angioplasty group had a higher first-pass recanalization rate than the preferred stent thrombectomy group (61.3% vs. 21.9%, P <0.001) and a higher proportion of patients who were functionally independent (defined as a modified Rankin Scale score of 0 to 3) at 90 days [odds ratio,3.681; 95% confidence interval (CI):1.009 to 13.428; P =0.048]. There was no significant difference between the groups in the time from puncture to recanalization, the frequency of successful reperfusion, and early neurological improvement, or intracranial hemorrhage ( P >0.05). This study suggests that for acute middle cerebral artery occlusion in ICAS, preferred angioplasty may be a safe and effective procedure.

Propensity score-adjusted analysis on early tirofiban administration to prevent thromboembolic complications during stand-alone coil embolization of ruptured aneurysms

The glycoprotein IIb/IIIa antagonist tirofiban has been shown to prevent thromboembolic events during endovascular procedures, but the benefits and risks of its prophylactic early intraprocedural administration for stand-alone coil embolization of acutely ruptured aneurysms are still unclear. We conducted a retrospective single-center analysis of patients treated for aneurysmal subarachnoid hemorrhage with stand-alone coil embolization. Two study cohorts were compared according to the primary prophylactic antithrombotic medication during the procedure: patients receiving only intravenous heparin (HEP) versus patients receiving tirofiban in addition to heparin prior to final aneurysm obliteration (HEP + TF). Outcome endpoints were the incidence of angiographically visible thrombus formation or distal embolization, and the incidence of periprocedural intracranial hemorrhage (ICH). Of 204 cases, 159 were prophylactically treated with HEP and 45 with HEP + TF. Intraprocedural thromboembolic events were less frequent with HEP + TF before and after propensity score matching (PSM) (2.5% vs. 19.7%, p = 0.017). The incidence of ICH and symptomatic ICH did not differ between HEP + TF and HEP before and after PSM (20.5% vs. 30.7%, p = 0.29; and 5.1% vs. 4%, p = 0.88). Early intraprocedural tirofiban administration may be effective in preventing thromboembolic complications during stand-alone coil embolization of acutely ruptured aneurysms without increasing the risk of ICH.

Efficacy and Safety of Direct Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation and Liver Cirrhosis.

Comparing direct oral anticoagulants (DOACs) and warfarin's efficacy and safety in patients with nonvalvular atrial fibrillation (AF) and liver cirrhosis (LC). Evidence of the pharmacodynamics of DOACs is limited in patients with AF and LC. A retrospective cohort study was conducted in the largest hospital system in Taiwan, involving patients with AF and LC for the years 2012 to 2021. Hazards of thromboembolic events (ischemic stroke, transient ischemic attack, and systemic embolism), intracranial hemorrhage, gastrointestinal, major bleeding, and all-cause mortality were investigated with a new-user, active comparator design. Inverse probability of treatment weighting was applied to balance potential confounders between treatment groups. In total, 478 DOAC users and 247 warfarin users were included. DOACs and warfarin demonstrated similar trends in preventing thromboembolic events, namely ischemic stroke [adjusted hazard ratio (aHR), 1.05 (95% CI: 0.42-2.61)], transient ischemic attack [aHR, 1.36 (95% CI: 0.18-10.31)], and systemic embolism [aHR, 0.49 (95% CI: 0.14-1.70)]. DOAC use was associated with a similar risk of intracranial hemorrhage [aHR, 0.65 (95% CI: 0.26-1.59)] and gastrointestinal bleeding [aHR, 0.64 (95% CI: 0.39-1.03)], a decreased risk of major bleeding [aHR, 0.64 (95% CI: 0.42-0.99)], and a reduction in mortality [aHR, 0.73 (95% CI: 0.54-0.99)]. DOAC users exhibited a significant reduction in major bleeding risk in patients with Child-Pugh class A (aHR, 0.48; 95% CI: 0.33-0.70). DOACs showed potential safety advantages over warfarin for patients with nonvalvular AF and LC, particularly in reducing major bleeding risk in those with Child-Pugh class A.

The ETNA-AF Europe registry: 4-year data of edoxaban use in atrial fibrillation in the Italian real world compared to the European cohort

The prospective, single-arm, observational, phase 4 ETNA-AF Europe study collected real-world data about safety, effectiveness and therapeutic adherence in European patients with non-valvular atrial fibrillation newly prescribed with edoxaban and followed up for 4 years. Overall, 13 164 patients were included in the full-analysis set, which means that they had at least one documentation after baseline at 4 years. The current paper reports about the 3329 Italian patients out of the whole European population. In the Italian cohort, median age was 76.0 (69.0-82.0) years, with 57.4% of the patients being ≥75 years old. The CHA2DS2-VASc score was >4 in 586 (18.1%) patients. At baseline, 670 (20.8%) patients were classified as frail by the investigators. Edoxaban 30 mg/day was prescribed to 1013 (31.8%) patients: these were older, with more comorbidities and a lower estimated creatinine clearance compared with those receiving 60 mg/day. All-cause mortality was 4.1%/year and there were very low yearly rates of bleeding and thromboembolic events: major bleeding, 0.9%; intracranial hemorrhage, 0.2%; ischemic stroke, 0.3%; systemic embolism, <0.1%. These events were more frequent in patients ≥75 years or in patients with renal impairment or treated with edoxaban 30 mg/day. Advancing age was not associated with an increased incidence of intracranial bleeding. These findings confirm the favorable long-term safety and effectiveness profile of edoxaban in non-valvular atrial fibrillation patients treated in routine clinical care in Italy.

Optimal timing of anticoagulation after acute ischaemic stroke with atrial fibrillation (OPTIMAS): a multicentre, blinded-endpoint, phase 4, randomised controlled trial

The optimal timing of anticoagulation for patients with acute ischaemic stoke with atrial fibrillation is uncertain. We investigated the efficacy and safety of early compared with delayed initiation of direct oral anticoagulants (DOACs) in patients with acute ischaemic stroke associated with atrial fibrillation. We performed a multicentre, open-label, blinded-endpoint, parallel-group, phase 4, randomised controlled trial at 100 UK hospitals. Adults with atrial fibrillation and a clinical diagnosis of acute ischaemic stroke and whose physician was uncertain of the optimal timing for DOAC initiation were eligible for inclusion in the study. We randomly assigned participants (1:1) to early (ie, ≤4 days from stroke symptom onset) or delayed (ie, 7-14 days) anticoagulation initiation with any DOAC, using an independent online randomisation service with random permuted blocks and varying block length, stratified by stroke severity at randomisation. Participants and treating clinicians were not masked to treatment assignment, but all outcomes were adjudicated by a masked independent external adjudication committee using all available clinical records, brain imaging reports, and source images. The primary outcome was a composite of recurrent ischaemic stroke, symptomatic intracranial haemorrhage, unclassifiable stroke, or systemic embolism incidence at 90 days in a modified intention-to-treat population. We used a gatekeeper approach by sequentially testing for a non-inferiority margin of 2 percentage points, followed by testing for superiority. OPTIMAS is registered with ISRCTN (ISRCTN17896007) and ClinicalTrials.gov (NCT03759938), and the trial is ongoing. Between July 5, 2019, and Jan 31, 2024, 3648 patients were randomly assigned to early or delayed DOAC initiation. 27 participants did not fulfil the eligibility criteria or withdrew consent to include their data, leaving 3621 patients (1814 in the early group and 1807 in the delayed group; 1981 men and 1640 women) in the modified intention-to-treat analysis. The primary outcome occurred in 59 (3·3%) of 1814 participants in the early DOAC initiation group compared with 59 (3·3%) of 1807 participants in the delayed DOAC initiation group (adjusted risk difference [RD] 0·000, 95% CI -0·011 to 0·012). The upper limit of the 95% CI for the adjusted RD was less than the non-inferiority margin of 2 percentage points (pnon-inferiority=0·0003). Superiority was not identified (psuperiority=0·96). Symptomatic intracranial haemorrhage occurred in 11 (0·6%) participants allocated to the early DOAC initiation group compared with 12 (0·7%) participants allocated to the delayed DOAC initiation group (adjusted RD 0·001, -0·004 to 0·006; p=0·78). Early DOAC initiation within 4 days after ischaemic stroke associated with atrial fibrillation was non-inferior to delayed initiation for the composite outcome of ischaemic stroke, intracranial haemorrhage, unclassifiable stroke, or systemic embolism at 90 days. Our findings do not support the current common and guideline-supported practice of delaying DOAC initiation after ischaemic stroke with atrial fibrillation. British Heart Foundation.

Tenecteplase versus alteplase for acute stroke within 4·5 h of onset (ATTEST-2): a randomised, parallel group, open-label trial

Tenecteplase has potential benefits over alteplase, the standard agent for intravenous thrombolysis in acute ischaemic stroke, because it is administered as a single bolus and might have superior efficacy. The ATTEST-2 trial investigated whether tenecteplase was non-inferior or superior to alteplase within 4·5 h of onset. We undertook a prospective, randomised, parallel-group, open-label trial with masked endpoint evaluation in 39 UK stroke centres. Previously independent adults with acute ischaemic stroke, eligible for intravenous thrombolysis less than 4·5 h from last known well, were randomly assigned 1:1 to receive intravenous alteplase 0·9 mg/kg or tenecteplase 0·25 mg/kg, by use of a telephone-based interactive voice response system. The primary endpoint was the distribution of the day 90 modified Rankin Scale (mRS) score and was analysed using ordinal logistic regression in the modified intention-to-treat population. We tested the primary outcome for non-inferiority (odds ratio for tenecteplase vs alteplase non-inferiority limit of 0·75), and for superiority if non-inferiority was confirmed. Safety outcomes were mortality, symptomatic intracranial haemorrhage, radiological intracranial haemorrhage, and major extracranial bleeding. The trial was prospectively registered on ClinicalTrials.gov (NCT02814409). Between Jan 25, 2017, and May 30, 2023, 1858 patients were randomly assigned to a treatment group, of whom 1777 received thrombolytic treatment and were included in the modified intention-to-treat population (n=885 allocated tenecteplase and n=892 allocated alteplase). The mean age of participants was 70·4 (SD 12·9) years and median National Institutes of Health Stroke Scale was 7 (IQR 5-13) at baseline. Tenecteplase was non-inferior to alteplase for mRS score distribution at 90 days, but was not superior (odds ratio 1·07; 95% CI 0·90-1·27; p value for non-inferiority<0·0001; p=0·43 for superiority). 68 (8%) patients in the tenecteplase group compared with 75 (8%) patients in the alteplase group died, symptomatic intracerebral haemorrhage (defined by SITS-MOST criteria) occurred in 20 (2%) versus 15 (2%) patients, parenchymal haematoma type 2 occurred in 37 (4%) versus 26 (3%) patients, post-treatment intracranial bleed occurred in 94 (11%) versus 78 (9%) patients, significant extracranial haemorrhage occurred in 13 (1%) versus six (1%) patients, respectively, and angioedema occurred in six (1%) participants in both groups. Tenecteplase 0·25 mg/kg was non-inferior to 0·9 mg/kg alteplase within 4·5 h of symptom onset in acute ischaemic stroke. Easier administration of tenecteplase, especially in the context of interhospital transfers, indicates that tenecteplase should be preferred to alteplase for thrombolysis in acute ischaemic stroke. The ATTEST-2 population was large and representative of thrombolysis-eligible patients in the UK and, together with findings from other trials, provides robust evidence supporting the introduction of tenecteplase in preference to alteplase. The Stroke Association and British Heart Foundation.

Plasmapheresis for extracorporeal membrane oxygenation (ECMO)-induced hemolysis in infants

Background: Intravascular hemolysis is a known complication of extracorporeal membrane oxygenation (ECMO). Characterized by elevated plasma-free hemoglobin (PFH), intravascular hemolysis is associated with cytotoxic effects leading to renal replacement therapy (RRT), longer ECMO runs and mortality. Therapeutic plasma exchange (TPE) in tandem with ECMO was described as a therapy for various pathologic conditions, but there are no ELSO guidelines for the treatment of ECMO-induced hemolysis. We describe the use of TPE in the management of severe ECMO-induced hemolysis. Methods: Two term neonates receiving veno-arterial (VA) ECMO developed severe PFH, with peak values over 500 mg/dL. TPE was performed in tandem with the ECMO circuit. Packed red cells were used to prime the TPE circuit, and citrate anticoagulation was added to establish the interface, which could not be achieved with existing heparin in the ECMO circuit. Therapy was completed with saline solution as a decoy for citrate, to avoid hypocalcemia and intracranial bleeding. Plasma volume was replaced by fresh frozen plasma (FFP). Results: In one patient PFH fell to 120 mg/dL, but rebounded to close to 500 mg/dL, only to stabilize between 210 and 300 mg/dL after the second TPE. He was liberated from ECMO, but could not survive a respiratory decompensation. The other patient’s PFH improved to 360 mg/dL after one TPE and continued to decline to 120 mg/dL over the ensuing days. Despite that improvement, care was withdrawn. Conclusion: TPE is effective in decreasing the burden of PFH, is well tolerated in tandem with ECMO, and a database of infants with ECMO-induced hemolysis needs to be created to assess the current practice, and establish clinical guidelines for its most appropriate therapy.

Efficacy and safety of tirofiban plus recombinant tissue plasminogen activator versus recombinant tissue plasminogen activator alone in acute ischemic stroke patients: a meta-analysis

ObjectiveTirofiban plus recombinant tissue plasminogen activator (rtPA) shows good efficacy and safety in treating acute ischemic stroke (AIS) patients, but there is a lack of comprehensive assessment. This meta-analysis aimed to compare the efficacy and safety of rtPA plus tirofiban with rtPA alone in AIS patients. MethodsThis meta-analysis retrieved studies comparing rtPA intravenous thrombolysis followed by tirofiban (rtPA+T group) versus rtPA intravenous thrombolysis alone (rtPA group) for AIS patients in Excerpt Medica Database, Web of Science, Cochrane, PubMed, China National Knowledge Infrastructure, Wanfang, and SinoMed until March 2024. ResultsTwenty studies with 2048 AIS patients were enrolled in this meta-analysis. National Institute of Health stroke scale (NIHSS) score after treatment was lower in the rtPA+T group than the rtPA group [standardized mean differences (SMD)=-1.41; 95% confidence interval (CI)=-1.83, -0.98; P<0.001]. The proportion of AIS patients achieving a favorable functional outcome (modified Rankin Scale score ≤2) was increased in the rtPA+T group versus the rtPA group [relative risk (RR)=1.13; 95% CI=1.05, 1.21; P=0.001]. The incidence of re-occlusion was lower in the rtPA+T group than in the rtPA group (RR=0.24; 95% CI=0.10, 0.59; P=0.002), but the incidence of intracranial hemorrhage (ICH) (RR=0.85; 95% CI=0.51, 1.43), symptomatic ICH (RR=1.10; 95% CI=0.43, 2.84), and mortality (RR=1.39; 95% CI=0.53, 3.65) was not different between the two groups (all P>0.05). The stability assessed by sensitivity analysis was good, and no publication bias was found. ConclusionrtPA plus tirofiban achieves superior efficacy with comparable safety profiles compared to rtPA alone in AIS patients.