Intracranial Hemorrhage Research Articles

Comparative Effects of Glenzocimab and Eptifibatide on Bleeding Severity in 2 Mouse Models of Intracranial Hemorrhage.

Antiplatelet drugs represent potential candidates for protecting the penumbral microcirculation during cerebral ischemia and improving the benefits of arterial recanalization in ischemic stroke. Yet while the efficacy of such adjuvant strategies has been shown to be highly time dependent, antiplatelet therapy at the acute phase of ischemic stroke cannot be envisioned until the diagnosis of stroke and its ischemic nature have been confirmed because of the presumed risk of worsening bleeding in case of intracranial hemorrhage (ICH). Here, we investigated this risk for 2 antiplatelet drugs currently being tested in clinical trials for ischemic stroke, glenzocimab and eptifibatide, in 2 mouse models of ICH. The severity of ICH was assessed in mice humanized for glycoprotein VI treated or not with glenzocimab or eptifibatide at effective dose, in a model of primary ICH caused by unilateral striatal injection of collagenase type VII, and in a model of hyperglycemia-induced hemorrhagic transformation of cerebral ischemia-reperfusion injury. Glenzocimab had no impact on bleeding severity in either model of ICH. Conversely, eptifibatide caused a significant increase in intracranial bleeding in both models, and a drastic increase in death after hyperglycemia-induced hemorrhagic transformation of cerebral ischemia-reperfusion injury. Unlike eptifibatide, glenzocimab is safe in the setting of ICH. These results suggest that glenzocimab could be administered upon suspicion of ischemic stroke, before assessment of its ischemic nature, thus opening the way to hastening of treatment initiation.

For Atrial Fibrillation, DOACs Outperform Warfarin in Patients with Reduced Kidney Function.

At standard doses, direct oral anticoagulants (DOACs) were associated with a reduced risk of systemic embolism and intracranial hemorrhage (ICH) when compared with warfarin, with a greater derived benefit at lower creatinine clearance (CrCl-down to 25 mL/min). Lower doses of DOACs were associated with increased overall mortality without a significant decrease in ICH and incident bleeding when compared with standard dose DOACs and warfarin, across all CrCl down to 25 mL/min.1.

Hemorrhagic Occipital Meningocele in Dandy Walker Syndrome: A Rare Case

Dandy walker syndrome is commonest congenital cerebellar malformation with estimated prevalence of 1:25,000 to 1:50.000 live births. However, its association with occipital meningocele is a rarely seen. Here we present an unusual case of preterm neonate with Dandy walker syndrome and occipital meningocele, intraventricular haemorrhage and haemorrhage within the posterior fossa cyst. The patient was diagnosed antenatally in the third trimester and had a vaginal delivery. Keywords: Dandy walker syndrome, Occipital meningocele, Intracranial haemorrhage

Optimal Duration of Dual Antiplatelet Therapy After Carotid Artery Stenting: A Nationwide Cohort Study.

Carotid artery stenting (CAS) is an alternative treatment for patients with carotid artery stenosis who are not eligible for carotid endarterectomy. Dual antiplatelet therapy (DAPT) after CAS aims to prevent ischemic stroke. However, its optimal duration remains unclear. We aimed to determine the optimal duration of DAPT by identifying the differences in clinical events that occur depending on the DAPT maintenance period. Data were obtained from the nationwide database of the Korean Health Insurance Review and Assessment Service between 2007 and 2019. Patients who received CAS, as identified by procedure codes, were divided into 2 groups according to the duration of DAPT (aspirin and clopidogrel): those who maintained DAPT for at least 90 days but for <6 months (short-DAPT group) and those who maintained it for longer (long-DAPT group). The primary outcome was a composite of ischemic stroke, gastrointestinal bleeding, and intracranial hemorrhage within 12 months of switching to single antiplatelet therapy. Statistical analyses used inverse probability of treatment weighting to balance baseline characteristics, with Cox regression and Fine and Gray competing risk models used to assess outcomes. Of the 12 034 patients who underwent CAS, 2529 and 9505 were assigned to the short-DAPT and long-DAPT groups, respectively. In the short-DAPT group, ischemic stroke, gastrointestinal bleeding, and intracranial hemorrhage occurred in 41 (1.6%), 22 (0.9%), and 4 (0.2%) patients, respectively. In the long-DAPT group, ischemic stroke, gastrointestinal bleeding, and intracranial hemorrhage occurred in 108 (1.1%), 87 (0.9%), and 4 (0.04%) patients, respectively. The primary outcome did not differ significantly between the groups (2.5% versus 2.1%; adjusted hazard ratio of long-DAPT to short-DAPT, 0.869 [95% CI, 0.652-1.158]; P=0.337). Short-duration DAPT can be recommended, as it does not differ from long-duration DAPT in terms of clinical efficacy and adverse events after CAS.

The effects of admission hyperglycemia and diabetes mellitus on mechanical thrombectomy outcomes: A systematic review and meta-analysis.

The impact of certain comorbidities on mechanical thrombectomy (MT) outcomes remains largely unexplored. Diabetes mellitus (DM) and admission hyperglycemia have been associated with poor clinical outcomes for patients treated with MT. In this study, we sought to investigate the effects of DM and admission hyperglycemia on MT outcomes. Following PRISMA guidelines, a systematic literature search was conducted in Medline, Embase, Scopus, and Web of Science databases. Data regarding successful recanalization (modified Thrombolysis in Cerebral Infarction [mTICI] ≥2b), functional independence (modified Rankin Scale [mRS] 0-2), excellent outcomes (mRS 0-1), symptomatic intracranial hemorrhage (sICH), and mortality were extracted from the included studies. The pooled odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were calculated using random effects model. Twenty-one studies comprising 9708 patients were included. A total of 2311 patients (24%) had a history of DM, and 2026 patients (21%) had admission hyperglycemia. Admission hyperglycemia was associated with significantly lower odds of mTICI ≥2b (OR = 0.7, 95% CI = 0.55-0.89), mRS 0-2 (OR = 0.47, 95% CI = 0.41-0.53), and mRS 0-1 (OR = 0.43, 95% CI = 0.34-0.55) as compared to normoglycemic state. Patients with hyperglycemia had significantly higher rates of sICH (OR = 2.05, 95% CI = 1.66-2.54) and mortality (OR = 1.99, 95% CI = 1.58-2.52) than normoglycemic patients. Diabetes mellitus was associated with significantly high rates of mortality (OR = 1.74, 95% CI = 1.31-2.3) and lower rates of mRS 0-2 (OR = 0.60, 95% CI = 0.48-0.76) in sensitivity analyses. Our results indicate that admission blood glucose levels and DM can negatively affect MT outcomes. Further research should focus on optimizing MT outcomes for these patients.

Early-Onset Seizures After Orthotopic Liver Transplantation: A Single-Center Retrospective Study.

After encephalopathy, epileptic seizures (ES) are the second most common neurologic complication after orthotopic liver transplantation (OLT) and may announce a disabling/fatal neurologic disease. In this retrospective study, we collected clinical information from patients who underwent OLT at our institution and analyzed outcomes and potential risk factors for developing ES after OLT. Fourteen of our 376 patients (3.72%) who underwent OLT had ES. After excluding 2 patients with already known epilepsy, among the other 12 patients, 2 were diagnosed with nonanoxic cerebral edema, 2 with anoxic damage, 1 with intracranial hemorrhage, 1 with metabolic derangement, and 4 with neurotoxicity; 2 did not receive a diagnosis of certainty. 9 of 12 patients had structural abnormalities on neuroimaging exams. Patients with ES had lower body mass index, higher rate of pretransplant portal thrombosis, and lower pre-transplant plasma concentration of albumin than patients without ES. Multiple post-transplantation systemic complications, postoperative infections, and graft rejection were correlated with a significantly higher risk of ES. Compared with patients without seizures, patients with ES had longer in-hospital and intensive care unit (ICU) length of stay, higher probability of ICU readmission, in-hospital death, and need for rehabilitation. Just 3 of the 12 patients with ES had a good prognosis, while the other 9 had at least mild neurologic sequelae, 5 of whom died because of the underlying neurologic disease. ES after OLT may announce detrimental neurologic disease. When an underlying neurologic disease is excluded, prognosis in terms of seizure recurrence and long-term antiseizure medication need is warranted.

Noninvasive Vagus Nerve Stimulation Protects Neurons in the Perihematomal Region and Improves the Outcomes in a Rat Model of Intracerebral Hemorrhage.

Intracranial hemorrhage (ICH) is a devastating stroke subtype with a high rate of mortality and disability. Therapeutic options available are primarily limited to supportive care and blood pressure control, whereas the surgical approach remains controversial. In this study, we explored the effects of noninvasive vagus nerve stimulation (nVNS) on hematoma volume and outcome in a rat model of collagenase-induced ICH. Adult male Wistar rats were randomized into two study groups: (1) ICH-treated (rats treated with five 2-min nVNS) and (2) ICH-control (ICH with sham nVNS). Each group received either a 0.1-U or a 0.2-U collagenase dose. After assessing neurological function, rats were euthanized at 24 h for spectrophotometric hemoglobin assay, hematoma volume measurements, and histological studies. The ICH-treated group that received the 0.1-U collagenase dose demonstrated significantly smaller hematoma volume and improved motor function compared with the ICH-control with the same dose. Furthermore, the pooled data for the ICH-treated groups (both 0.1 U and 0.2 U of collagenase) revealed a reduction in neuronal loss in the perihematomal region in the histopathological studies. This effect was not significant for the group that received a 0.2-Ucollagenase dose. nVNS therapy in acute settings may provide a neuroprotective effect and limit hematoma expansion in smaller volumes, improving neurological function post-ICH.

The variable relationship between the National Early Warning Score on admission to hospital, the primary discharge diagnosis, and in-hospital mortality.

Patients with an elevated admission National Early Warning Score (NEWS) are more likely to die while in hospital. However, it is not known if this increased mortality risk is the same for all diagnoses. The aim of this study was to determine and compare the increased risk of in-hospital mortality associated with an elevated NEWS and different primary discharge diagnoses in unselected emergency admissions to a UK university teaching hospital. A non-interventional observational study of 122,321 consecutive, unselected, adult patients with complete data admitted as an emergency between 2014 and 2022. The overall in-hospital mortality was 4.3%. Eighty diagnostic groupings accounted for 85.8% of all admissions and 89.4% of all in-hospital deaths. Depending on diagnostic grouping, the risk of mortality associated with an admission NEWS ≥ 3 ranged from 2.3- to 100-fold. For example, the in-hospital mortality of COPD patients increased from 1.9% for those with admission NEWS < 3 to 35.6% for those with NEWS ≥ 3, for chest pain mortality increased from 0.1 to 3.9%, and for patients with an opiate overdose from 0.2 to 7.7%. Conversely, for admission NEWS < 3, aspiration pneumonia and intracranial hemorrhage had in-hospital mortalities of 13.7% and 12.1%, respectively. There is enormous variation in the mortality risk associated with an increased admission NEWS in different commonly encountered diagnoses. Therefore, the mortality risk of some 'low risk' conditions can be dramatically increased if their admission NEWS is elevated, whereas some 'high risk' conditions are still likely to die even if their admission NEWS is low.

Association Between Time to Treatment and Outcomes of Endovascular Therapy vs Medical Management in Patients With Large Ischemic Stroke.

Randomized trials have proven the benefit of endovascular therapy (EVT) for acute large ischemic stroke. This study was to characterize the effect of time to treatment on benefit of EVT vs medical management (MM) among patients with large ischemic stroke. This was a post hoc analysis of the Endovascular Therapy in Acute Anterior Circulation Large Vessel Occlusive Patients with a Large Infarct Core randomized trial. Patients who had an Alberta Stroke Program Early Computed Tomography Score of 3-5 or an ischemic core volume of 70-100 mL within 24 hours of symptom onset were treated with EVT plus MM or MM. Onset-to-expected arterial puncture time (OPT) was analyzed as a categorical variable (<6, 6-<12, and 12-24 hours) using binary logistic regression and as a continuous variable using a multivariable fractional polynomial interaction. The primary efficacy outcome was favorable outcomes (modified Rankin Scale scores 0-3) at 90 days. Safety outcomes included any intracranial hemorrhage (ICH), symptomatic ICH, and mortality. Among 451 patients (median age 68 years; 61.4% were men; median OPT 487 minutes [interquartile range 328-802]), 226 patients received EVT and 225 patients received MM. The EVT group showed higher rates of favorable outcomes than the MM group within OPT of 6 hours (44.4% vs 29.9%, adjusted odds ratio [aOR] 2.78, 95% CI 1.22-6.32) and 6-12 hours (45.7% vs 29.6%, aOR 2.39 [95% CI 1.21-4.71]), but not in OPT beyond 12 hours (51.6% vs 41.4%, aOR 2.05 [95% CI 0.88-4.77]). The benefit became nonsignificant after OPT of 13 hours and 22 minutes. In 3 OPT intervals, the rates of symptomatic ICH and mortality were similar between EVT and MM although the rate of any ICH increased. However, no interaction effect was found (all p interactions >0.10). These findings strengthen the benefit of EVT initiated within 13 hours and 22 minutes after symptom onset compared with MM alone in patients with large ischemic stroke, but EVT should not be withheld for patients presenting beyond 13 hours and 22 minutes. Pooled analysis of larger sample sizes is needed. ClinicalTrials.gov; NCT04551664. This study provides Class II evidence that EVT is associated with improved functional outcomes for acute large ischemic stroke within 24 hours after last known well, with no interaction by time.

Early vs Late Anticoagulation After Ischemic Stroke in Patients With Atrial Fibrillation and Covert Brain Infarcts.

Covert brain infarcts (CBIs) in patients with first-ever ischemic stroke (IS) and atrial fibrillation (AF) are associated with an increased risk of stroke recurrence. We aimed to assess whether CBIs modify the treatment effect of early vs late initiation of direct oral anticoagulants (DOACs) in patients with IS and AF. We conducted a post hoc analysis of the international, multicenter, randomized-controlled ELAN trial, which compared early (<48 hours after ischemic stroke for minor and moderate stroke, 6-7 days for major stroke) vs late (>48 hours for minor, 3-4 days for moderate, 12-14 days for major stroke) initiation of DOACs in patients with IS and AF. The primary outcome was a composite of recurrent IS, symptomatic intracranial hemorrhage (sICH), major extracranial bleeding, systemic embolism, or vascular death within 30 days after stroke; secondary outcomes were the individual components. We estimated outcomes based on the presence of CBIs (any CBI vs no CBI) on prerandomization imaging (core-lab rating) using adjusted risk differences (aRDs) between treatment arms. Point estimates and 95% CIs are presented without reporting p values. Of the 1,694 participants with first-ever IS included (median age: 77 years, 45.9% female), 678 (40.0%) had CBI. The imaging core-lab interrater reliability for the presence of CBI was 0.87 (0.81-0.94). The primary outcome occurred in 8 (2.3%; recurrent IS: 3/342) of 342 participants with CBI assigned to the early treatment arm vs 20 (6.0%; recurrent IS: 12/336) of 336 assigned to the late treatment arm (aRD: -3.6%, 95% CI -6.6 to -0.6) (p for interaction: 0.063). With early DOAC treatment, IS recurrence risk was lower in participants with CBI (aRD: -2.7%, 95% CI -5.0 to -0.4), but not in participants without CBI (aRD: -0.4, 95% CI -2.1 to 1.2). No sICH was observed in the early treatment group. The presence of CBI may indicate a subgroup of patients with first-ever IS and AF who particularly benefits from early DOAC initiation to prevent ischemic event recurrence, without increasing harm. Our findings should be considered in clinical decision making regarding timely DOAC treatment in patients with stroke and AF. This study provides Class II evidence that in patients with covert brain infarcts, atrial fibrillation, and first-ever ischemic stroke, early (vs late) initiation of DOACs is associated with lower risk of recurrent stroke with no increase in harm. URL: clinicaltrials.gov/study/NCT03148457; Unique identifier: NCT03148457; submitted: April 7, 2017; first patient enrolled: November 6, 2017.

Intra-arterial tenecteplase after successful endovascular recanalisation in patients with acute posterior circulation arterial occlusion (ATTENTION-IA): multicentre randomised controlled trial

ObjectiveTo assess whether intra-arterial tenecteplase administered after successful endovascular recanalisation improves outcomes in patients with acute arterial occlusion of the posterior circulation.DesignMulticentre randomised controlled trial.Setting31 hospitals in China, 24 January...

Intra-Arterial Urokinase After Endovascular Reperfusion for Acute Ischemic Stroke

Persisting or new thrombi in the distal arteries and the microcirculation have been reported to limit the benefits of successful endovascular thrombectomy for patients with acute ischemic stroke. It remains uncertain whether intra-arterial thrombolysis by urokinase following near-complete to complete reperfusion by thrombectomy improves outcomes among patients with ischemic stroke due to large vessel occlusion. To assess the efficacy and adverse events of intra-arterial urokinase after near-complete to complete reperfusion by thrombectomy for acute ischemic stroke due to large vessel occlusion. This investigator-initiated, randomized, open-label, blinded-end point trial was implemented at 35 hospitals in China, enrolling 535 patients with proximal intracranial large vessel occlusion presenting within 24 hours of time last known well, who achieved near-complete or complete reperfusion by endovascular thrombectomy and did not receive intravenous thrombolysis prior to the procedure. Recruitment took place between November 15, 2022, and March 29, 2024, with final follow-up on July 4, 2024. Eligible patients were randomly assigned to the intra-arterial urokinase group (a single dose of intra-arterial 100 000 IU urokinase injected in the initial target territory; n = 267) or control group (without intra-arterial thrombolysis; n = 267). The primary efficacy outcome was the percentage of patients achieving survival without disability (modified Rankin Scale score of 0 or 1) at 90 days. The primary safety outcomes were mortality at 90 days and incidence of symptomatic intracranial hemorrhage within 48 hours. A total of 535 patients were enrolled (median age, 69 years; 223 [41.8%] female) and 532 (99.6%) completed the trial. The percentage of patients with survival without disability at 90 days was 45.1% (120/266) in the intra-arterial urokinase group and 40.2% (107/266) in the control group (adjusted risk ratio, 1.13 [95% CI, 0.94-1.36]; P = .19). Mortality at 90 days (18.4% vs 17.3%, respectively; adjusted hazard ratio, 1.06 [95% CI, 0.71-1.59]; P = .77) and incidence of symptomatic intracranial hemorrhage (4.1% vs 4.1%, respectively; adjusted risk ratio, 1.05 [95% CI, 0.45-2.44]; P = .91) were not significantly different between groups. Among patients with acute ischemic stroke due to large vessel occlusion, adjunct intra-arterial urokinase after near-complete to complete reperfusion by endovascular thrombectomy did not significantly increase the likelihood of survival without disability at 90 days. ChiCTR.org.cn Identifier: ChiCTR2200065617.

Intra-Arterial Tenecteplase Following Endovascular Reperfusion for Large Vessel Occlusion Acute Ischemic Stroke

The impact of adjunctive intra-arterial tenecteplase administration following near-complete to complete reperfusion by endovascular thrombectomy (EVT) for acute ischemic stroke is unknown. To assess the efficacy and adverse events of adjunctive intra-arterial tenecteplase in patients with large vessel occlusion stroke who had achieved near-complete to complete reperfusion (defined as a score on the expanded Thrombolysis in Cerebral Infarction [eTICI] scale of 2c to 3) after EVT. Investigator-initiated, randomized, open-label, blinded outcome assessment trial implemented at 34 hospitals in China among 540 patients with stroke due to proximal intracranial large vessel occlusion within 24 hours of the time they were last known to be well, with an eTICI score of 2c to 3 after EVT, and without prior intravenous thrombolysis. Recruitment took place between October 26, 2022, and March 1, 2024, with final follow-up on June 3, 2024. Eligible patients were randomly assigned to receive intra-arterial tenecteplase (n = 269) at 0.0625 mg/kg or no intra-arterial thrombolysis (control group; n = 271). The primary efficacy outcome was freedom from disability, defined as a score of 0 or 1 on the modified Rankin Scale (range, 0 [no symptoms] to 6 [death]) at 90 days. The primary safety outcomes were death at 90 days and symptomatic intracranial hemorrhage within 48 hours. A total of 539 participants (99.8%) completed the trial (median age, 69 years; 221 female [40.9%]). The proportion with a modified Rankin Scale score of 0 or 1 at 90 days was 49.1% (132/269) in the intra-arterial tenecteplase group and 44.1% (119/270) in the control group (adjusted risk ratio, 1.15 [95% CI, 0.97-1.36]; P = .11). Ninety-day mortality was 16.0% and 19.3% (adjusted hazard ratio, 0.75 [95% CI, 0.50-1.13]; P = .16), respectively. The proportions of symptomatic intracranial hemorrhage were 6.3% and 4.4% (adjusted risk ratio, 1.43 [95% CI, 0.68-2.99]; P = .35), respectively. In patients with acute ischemic stroke due to large vessel occlusion presenting within 24 hours of time last known to be well and who had achieved near-complete to complete reperfusion after EVT, adjunctive intra-arterial tenecteplase did not significantly increase the likelihood of freedom from disability at 90 days. ChiCTR.org.cn Identifier: ChiCTR2200064809.

Hospital admission of older patients with mild traumatic brain injury and traumatic intracranial hemorrhage: is it always necessary?

Background and importanceTraumatic intracranial hemorrhage (tICH) after mild traumatic brain injury (mTBI) is not uncommon in the elderly. Often, these patients are admitted to the hospital for observation. The necessity of admission in the absence of clinically important intracranial injuries is however unclear.ObjectivesThe objective of this study is to identify which factors additional to tICH affect the risk of this outcome and to evaluate the differences in the risk of adverse outcome in younger and older mTBI patients with tICH.Design, setting, and participantsThis retrospective study assessed adult (≥ 16 years) mTBI patients with tICH admitted to a Level 1 trauma center between January 2017 and October 2020.Outcome measures and analysisPatients were stratified into two groups, age < 65 years and age ≥ 65 years. Adverse outcome due to tICH was assessed using a composite adverse outcome which comprised either, a drop in GCS by more than 1 point, progression of or new neurological deficits, seizure activity, progression of tICH on repeated neuroimaging after clinical deterioration, a neurosurgical intervention, a readmission within three months of injury related to TBI, or death. Logistic regression analysis was used to identify independent predictors of the composite adverse outcome.Main resultsIn total, 332 mTBI patients with tICH were enrolled in our study. Older mTBI patients with tICH met the criteria for the composite adverse outcome significantly more often than younger patients (12.6% 95% CI 8.0–17.0% vs. 4.9%, 95% CI 1.0–9.0%, p = 0.033). The univariate analysis showed that a neurological deficit (OR 6.55, 95% CI 2.37–18.08) or a SDH on admission (OR 3.13, 95% CI 1.40–6.99) was positively associated with the composite adverse outcome in older patients. The presence of isolated traumatic SAH (tSAH) was associated with a decreased risk of the composite adverse outcome (OR 0.10, 95% CI 0.01–0.71). Multivariate analysis was not possible.ConclusionSerious adverse outcomes are frequently observed in older mTBI patients with tICH. Nonetheless, our findings suggest that older patients with an isolated tSAH are at low-risk for deterioration and may be directly discharged from the ED after a short period of observation.

Potential interactions between antimicrobials and direct oral anticoagulants: population-based cohort and case-crossover study.

Although drug interactions between clarithromycin/erythromycin/fluconazole and direct oral anticoagulants (DOACs) are mechanistically plausible, it is uncertain whether they are clinically relevant. To investigate the association between co-prescribed DOACs and antimicrobials and bleeding, cardiovascular disease and mortality. We identified DOAC users in the Clinical Practice Research Datalink Aurum from 1/1/2011-29/3/2021. We used a cohort design to estimate hazard ratios for bleeding outcomes (intracranial bleeding, gastrointestinal bleeding, other bleeding), comparing DOACs+clarithromycin/erythromycin/fluconazole users with DOACs users not receiving these antimicrobials. Cardiovascular outcomes were ischaemic stroke, myocardial infarction, venous thromboembolism, cardiovascular mortality and all-cause mortality. A 6-parameter case-crossover design comparing odds of exposure to different drug initiation patterns for all outcomes in hazard window versus referent window within an individual was also conducted. Of 483,815 DOAC users, we identified 21,701 co-prescribed clarithromycin, 4,532 co-prescribed erythromycin and 4,840 co-prescribed fluconazole. We observed an increased risk of gastrointestinal bleeding over 7-days following co-prescription of DOAC+erythromycin versus DOAC alone (HR:3.66; 99%CI:1.27-10.51), with wide CIs in case-crossover analysis. No evidence of increased risk of bleeding outcomes was seen for DOAC+clarithromycin/fluconazole in cohort and case-crossover analyses. For cardiovascular outcomes, compared with DOAC alone, an increased risk of cardiovascular mortality with DOAC+clarithromycin(HR:3.36; 99%CI:1.73-6.52) and increased risk of all-cause mortality with DOAC+clarithromycin/erythromycin/fluconazole were observed in cohort analysis. However, similar risks were found when initiating erythromycin/fluconazole with and without DOAC. We found no strong evidence of increased risks of bleeding and cardiovascular outcomes in DOACs+clarithromycin/fluconazole/erythromycin users except a possible short-term increased risk of gastrointestinal bleeding in DOACs+erythromycin users.

Risk of Symptomatic Intracranial Hemorrhage After Mechanical Thrombectomy in Randomized Clinical Trials: A Systematic Review and Meta-Analysis

Background: Symptomatic intracranial hemorrhage (sICH) is the most dreaded complication after reperfusion therapy for acute ischemic stroke. We performed a meta-analysis of randomized controlled trials to estimate and compare risks of sICH after mechanical thrombectomy (MT) depending on the location of the large vessel occlusion, concomitant use of intravenous thrombolysis, timing of treatment, and core size. Methods: Randomized controlled trials were included, following a comprehensive search of different databases from inception to 1 March 2024. Random-effect models in a meta-analysis were employed to obtain the pooled risk ratios (RRs) and their corresponding 95% confidence intervals (95% CI) for sICH with MT, and were then compared to other reperfusion treatment regimens, including best medical treatment and intravenous thrombolysis (IVT). Results: MT in the anterior circulation was associated with a significantly higher risk of sICH as compared with no-MT (RR: 1.46; 95%CI: 1.03–2.07; p = 0.037). The risk of sICH was comparable between the MT and MT+IVT groups (RR: 0.77; 95%CI: 0.57–1.03; p = 0.079). There was no difference in sICH risk with MT as compared with no-MT within 6 h of last known well (RR: 1.14; 95%CI: 0.78–1.66; p = 0.485) and beyond that time (RR: 1.29; 95%CI: 0.80–2.08; p = 0.252); the risk of sICH was also comparable between MT conducted within 6 h of last known well and MT conducted beyond that time (p = 0.512). The sICH risk for MT in the posterior circulation (RR: 7.48; 95%CI: 2.27–24.61) was significantly higher than for MT in the anterior circulation (RR: 1.18; 95%CI: 0.90–1.56) (p = 0.003). MT was also associated with a significantly higher sICH risk than no-MT among patients with large core strokes (RR: 1.71; 95%CI: 1.09–2.66, p = 0.018). Conclusions: When evaluating cumulative evidence from randomized controlled trials, the risk of sICH is increased after MT compared with patients not treated with MT. Yet, the difference is largely driven by the greater risk of sICH in patients treated with MT for posterior circulation occlusions and, to a lesser degree, large core strokes. Concomitant use of intravenous thrombolysis and the use of MT in the extended therapeutic window do not raise the risk of sICH.

Epistaxis Versus Nonepistaxis Bleeding in Anticoagulated Patients With Atrial Fibrillation: Results From the ENGAGE AF-TIMI 48 Trial.

Epistaxis is common with antithrombotic therapy and is often troublesome to patients, yet its frequency, severity, and outcomes are poorly characterized. Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) randomized 21 105 patients with atrial fibrillation and CHADS2 risk score ≥2 to higher-dose edoxaban regimen (60 mg daily, dose-reduced to 30 mg), lower-dose edoxaban regimen (30 mg, dose reduced to 15 mg, daily), or warfarin. Bleeds were adjudicated using International Society on Thrombosis and Haemostasis criteria. Patients with intracranial hemorrhage during follow-up were excluded; those with >1 bleeding event were categorized according to their most severe event. The safety cohort with interval censoring during drug interruption was analyzed. Proportions were compared using Pearson's chi-square test and treatment arms were compared using a Cox proportional hazards model. Among 5247 patients with a bleeding event, 1008 (19.2%) had epistaxis and 4239 (80.8%) had nonepistaxis bleeding. Epistaxis events were less severe than nonepistaxis bleeds (International Society on Thrombosis and Haemostasis major: 3.2% versus 20.7%; clinically relevant nonmajor: 64.7% versus 60.1%; minor: 32.1% versus 19.2%; P<0.001). Permanent drug discontinuation was similar following epistaxis versus nonepistaxis bleeding in patients with major (59.4% versus 53.6%; P=0.52) or clinically relevant nonmajor (32.5% versus 33.3%; P=0.70) bleeding but was significantly higher in patients with minor epistaxis versus other minor bleeds (33.3% versus 23.9%; P=0.001). Compared with warfarin, higher-dose edoxaban regimen had similar risk of epistaxis (hazard ratio [HR], 1.09 [95% CI, 0.95-1.26]), whereas lower-dose edoxaban regimen conferred reduced risk (HR, 0.73 [95% CI, 0.62-0.86]). Epistaxis was frequent, and despite being overall less severe than nonepistaxis bleeding, was associated with similar rates of anticoagulant discontinuation. Compared with warfarin, lower-dose edoxaban regimen reduced the risk of epistaxis by 27% whereas higher-dose edoxaban regimen had no effect. URL: https://clinicaltrials.gov; Unique Identifier: NCT00781391.

Metabolic pathway and genetically causal links of 1,400 circulating metabolites on the risk of intracranial aneurysms and aneurysmal subarachnoid hemorrhage.

The rupture of intracranial aneurysms (IAs) leads to aneurysmal subarachnoid hemorrhage (aSAH), which is associated with significant disability and mortality rates. This study aims to identify metabolic markers causally linked to the occurrence of IAs and aSAH through Mendelian randomization (MR), thereby offering novel predictive and therapeutic targets. We conducted a genome-wide association study (GWAS) on IAs and aSAH, analyzing 1,400 metabolomic indices from the Canadian Longitudinal Study on Aging (CLSA) cohort (n = 8,299). Subsequently, we employed two-sample Mendelian randomization to ascertain potential causal relationships between each metabolite and the conditions IAs and aSAH by various MR methodologies, including MR Egger, Weighted median, Inverse variance weighted (IVW), MR-PRESSO, Simple mode, and Weighted mode. The heterogeneity of instrumental variables was assessed using Cochran's Q statistics, and metabolic pathway analyses were performed via the Metaconflict 5.0 platform. Our analysis found that 87 metabolites/metabolic ratios were associated with IAs, and 85 metabolites/metabolic ratios were associated with aSAH. After false discovery rate (FDR) correction and sensitivity analyses, nine metabolites/metabolic ratios were significantly causally associated with aSAH. Conversely, while 87 metabolites and their ratios initially showed potential causal links with IA, none demonstrated significant causal associations post-FDR correction. The study also pinpointed eight significant metabolic pathways implicated in both IAs and aSAH. This study found that nine circulating metabolites and their ratios with significant causal associations to aSAH, while no metabolites and their ratios were causally linked to IAs. These results suggest possible mechanisms and predictive molecular targets for IAs and aSAH.

Bridging thrombolysis versus direct endovascular treatment in acute vertebrobasilar artery complex occlusion.

Endovascular treatment (EVT) is an effective treatment for patients with acute vertebrobasilar artery complex occlusion (VBAO). However, the benefit of bridging thrombolysis prior to EVT remains controversial. The purpose of the present study is to explore the best treatment strategy between bridging treatment (BT) and direct EVT in patients with acute VBAO. Patients with acute VBAO who underwent EVT within 24 hours of estimated occlusion in a nationwide retrospective registry at 65 stroke centers in 15 provinces in China from December 2015 to June 2022 were retrospectively analyzed. The outcomes of the BT and direct EVT groups were compared using propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). The primary outcome was favorable functional outcome, defined as a 90-day modified Rankin Scale (mRS) score of 0-3. Secondary outcomes included 90-day functional independence (mRS score 0-2), mRS score shift, in-hospital mortality, successful reperfusion, and symptomatic intracranial hemorrhage (sICH). In addition, a meta-analysis integrating currently available evidence was performed to make a systematic comparison between the two treatment strategies. A total of 2353 patients were ultimately included; 447 of these patients received BT and 1906 received direct EVT. In both the original cohort and in the 1:1 PSM analysis, patients in the BT group had a significantly higher rate of favorable functional outcome (adjusted odds ratio [aOR] 1.41, 95% CI 1.14-1.76 for the original cohort and aOR 1.44, 95% CI 1.07-1.92 for 1:1 PSM). Regarding secondary outcomes, patients with BT had a significantly lower rate of in-hospital mortality (aOR 0.67, 95% CI 0.51-0.88 for the original cohort and aOR 0.69, 95% CI 0.48-0.99 for 1:1 PSM) and a shift toward better outcomes on the mRS (aOR 1.35, 95% CI 1.12-1.63 for the original cohort and aOR 1.31, 95% CI 1.03-1.69 for 1:1 PSM). However, there were no significant differences in functional independence, successful reperfusion, and sICH between the two groups. A meta-analysis, which included 22 studies involving 6579 patients, also revealed the superiority of BT over direct EVT on favorable functional outcome (OR 1.19, 95% CI 1.03-1.37, I2 = 0.00%; p = 0.02). This matched-control study and meta-analysis suggest that compared with direct EVT, BT may be associated with better functional outcomes in patients with acute VBAO treated within 24 hours of estimated occlusion.

Safety of direct oral anticoagulants in hemodialysis patients with venous thromboembolism: an analysis using the Korean National Health Insurance Service database.

Limited data exist regarding the safety of direct oral anticoagulants in hemodialysis patients with venous thromboembolic disease. This study aims to investigate the safety of direct oral anticoagulants in hemodialysis patients using national data. The National Health Insurance Service database was retrospectively queried to identify chronic kidney disease patients who took direct oral anticoagulants for venous thromboembolism from 2008 to 2019. Bleeding complications and all-cause mortality were compared between 118 hemodialysis patients (HD group) and 227 matched chronic kidney disease patients not undergoing hemodialysis (CKD group). The use of direct oral anticoagulants among chronic kidney disease patients, with or without dialysis, increased over time. The incidence rate of all-cause mortality per 100 person-years was 38.1 in the HD group and 10.5 in the CKD group (adjusted hazard ratio [HR], 3.28; 95% confidence interval [CI], 2.27-4.75; p < 0.001). When considering death as a competing risk, there was no significant difference in gastrointestinal bleeding (adjusted HR, 1.61; 95% CI, 0.91-2.88; p = 0.115) and intracranial bleeding (adjusted HR, 1.86; 95% CI, 0.73-4.74; p = 0.193) between the HD and CKD groups. In comparison to chronic kidney disease patients not on hemodialysis, the major bleeding risk, including gastrointestinal and intracranial bleeding, was comparable in hemodialysis patients using direct oral anticoagulants for venous thromboembolism.