Rationale and Design of the Statins Use in Intracerebral Hemorrhage Patients (SATURN) Trial.

INTRODUCTION: The benefits and risks of HMG-CoA reductase inhibitor (statin) drugs in survivors of intracerebral hemorrhage (ICH) are unclear. Observational studies suggest an association between statin use and increased risk of lobar ICH, particularly in patients with apolipoprotein-E (APOE) ε2 and ε4 genotypes. There are no randomized controlled trials (RCTs) addressing the effects of statins after ICH leading to uncertainty as to whether statins should be used in patients with lobar ICH who are at high risk for ICH recurrence. The SATURN trial aims to evaluate the effects of continuation versus discontinuation of statin on the risk of ICH recurrence and ischemic major adverse cerebro-cardio-vascular events (MACCE) in patients with lobar ICH. Secondary aims include the assessment of whether the APOE genotype modifies the effects of statins on ICH recurrence, functional and cognitive outcomes and quality of life. METHODS: The SATURN trial is a multi-center, pragmatic, prospective, randomized, open-label, Phase III clinical trial with blinded end-point assessment. A planned total of 1456 patients with lobar ICH will be recruited from 140 sites in the United States, Canada and Spain. Patients presenting within seven days of a spontaneous lobar ICH that occurred while taking a statin, will be randomized (1:1) to continuation (control) vs. discontinuation (intervention) of the same statin drug and dose that they were using at ICH onset. The primary outcome is the time to recurrent symptomatic ICH within a two-year follow-up period. The primary safety outcome is the occurrence of ischemic MACCE. CONCLUSION: The results will help to determine the best strategy for statin use in survivors of lobar ICH and may help to identify if there is a subset of patients who would benefit from statins.

Transcarotid Arterial Revascularization of Symptomatic Internal Carotid Artery Disease: A Systematic Review and Study-Level Meta-Analysis.

BACKGROUND: Transcarotid artery revascularization (TCAR) is an interventional therapy for symptomatic internal carotid artery disease. Currently, the utilization of TCAR is contentious due to limited evidence. In this study, we evaluate the safety and efficacy of TCAR in patients with symptomatic internal carotid artery disease compared with carotid endarterectomy (CEA) and carotid artery stenting (CAS). METHODS: A systematic review was conducted, spanning from January 2000 to February 2023, encompassing studies that used TCAR for the treatment of symptomatic internal carotid artery disease. The primary outcomes included a 30-day stroke or transient ischemic attack, myocardial infarction, and mortality. Secondary outcomes comprised cranial nerve injury and major bleeding. Pooled odds ratios (ORs) for each outcome were calculated to compare TCAR with CEA and CAS. Furthermore, subgroup analyses were performed based on age and degree of stenosis. In addition, a sensitivity analysis was conducted by excluding the vascular quality initiative registry population. RESULTS: A total of 7 studies involving 24 246 patients were analyzed. Within this patient cohort, 4771 individuals underwent TCAR, 12 350 underwent CEA, and 7125 patients underwent CAS. Compared with CAS, TCAR was associated with a similar rate of stroke or transient ischemic attack (OR, 0.77 [95% CI, 0.33-1.82]) and myocardial infarction (OR, 1.29 [95% CI, 0.83-2.01]) but lower mortality (OR, 0.42 [95% CI, 0.22-0.81]). Compared with CEA, TCAR was associated with a higher rate of stroke or transient ischemic attack (OR, 1.26 [95% CI, 1.03-1.54]) but similar rates of myocardial infarction (OR, 0.9 [95% CI, 0.64-1.38]) and mortality (OR, 1.35 [95% CI, 0.87-2.10]). CONCLUSIONS: Although CEA has traditionally been considered superior to stenting for symptomatic carotid stenosis, TCAR may have some advantages over CAS. Prospective randomized trials comparing the 3 modalities are needed.

Intravenous Thrombolysis for Acute Ischemic Stroke in Patients With Recent Direct Oral Anticoagulant Use: A Systematic Review and Meta-Analysis.

BACKGROUND: Intravenous thrombolysis (IVT) is an effective stroke therapy that remains underused. Currently, the use of IVT in patients with recent direct oral anticoagulant (DOAC) intake is not recommended. In this study we aim to investigate the safety and efficacy of IVT in patients with acute ischemic stroke and recent DOAC use. METHODS AND RESULTS: A systematic review and meta-analysis of proportions evaluating IVT with recent DOAC use was conducted. Outcomes included symptomatic intracranial hemorrhage, any intracranial hemorrhage, serious systemic bleeding, and 90-day functional independence (modified Rankin scale score 0-2). Additionally, rates were compared between patients receiving IVT using DOAC and non-DOAC by a random effect meta-analysis to calculate pooled odds ratios (OR) for each outcome. Finally, sensitivity analysis for idarucizumab, National Institutes of Health Stroke Scale, and timing of DOAC administration was completed. Fourteen studies with 247 079 patients were included (3610 in DOAC and 243 469 in non-DOAC). The rates of IVT complications in the DOAC group were 3% (95% CI, 3-4) symptomatic intracranial hemorrhage, 12% (95% CI, 7-19) any ICH, and 0.7% (95%CI, 0-1) serious systemic bleeding, and 90-day functional independence was achieved in 57% (95% CI, 43-70). The rates of symptomatic intracranial hemorrhage (3.4 versus 3.5%; OR, 0.95 [95% CI, 0.67-1.36]), any intracranial hemorrhage (17.7 versus 17.3%; OR, 1.23 [95% CI, 0.61-2.48]), serious systemic bleeding (0.7 versus 0.6%; OR, 1.27 [95% CI, 0.79-2.02]), and 90-day modified Rankin scale score 0-2 (46.4 versus 56.8%; OR, 1.21 [95% CI, 0.400-3.67]) did not differ between DOAC and non-DOAC groups. There was no difference in symptomatic intracranial hemorrhage rate based on idarucizumab administration. CONCLUSIONS: Patients with acute ischemic stroke treated with IVT in recent DOAC versus non-DOAC use have similar rates of hemorrhagic complications and functional independence. Further prospective randomized trials are warranted.

Uric Acid: A Translational Journey in Cerebroprotection That Spanned Preclinical and Human Data.

Uric acid (UA) is a strong endogenous antioxidant that neutralizes the toxicity of peroxynitrite and other reactive species on the neurovascular unit generated during and after acute brain ischemia. The realization that a rapid reduction of UA levels during an acute ischemic stroke was associated with a worse stroke outcome paved the way to investigate the value of exogenous UA supplementation to counteract the progression of redox-mediated ischemic brain damage. The long translational journey for UA supplementation recently reached a critical milestone when the results of the multicenter NIH stroke preclinical assessment network (SPAN) were reported. In a novel preclinical paradigm, 6 treatment candidates including UA supplementation were selected and tested in 6 independent laboratories following predefined criteria and strict methodological rigor. UA supplementation was the only intervention in SPAN that exceeded the prespecified efficacy boundary with male and female animals, young mice, young rats, aging mice, obese mice, and spontaneously hypertensive rats. This unprecedented achievement will allow UA to undergo clinical testing in a pivotal clinical trial through a NIH StrokeNet thrombectomy endovascular platform created to assess new treatment strategies in patients treated with mechanical thrombectomy. UA is a particularly appealing adjuvant intervention for mechanical thrombectomy because it targets the microcirculatory hypoperfusion and oxidative stress that limits the efficacy of this therapy. This descriptive review aims to summarize the translational development of UA supplementation, highlighting those aspects that likely contributed to its success. It includes having a well-defined target and mechanism of action, and an approach that simultaneously integrated rigorous preclinical assessment, with epidemiologic and preliminary human intervention studies. Validation of the clinical value of UA supplementation in a pivotal trial would confirm the translational value of the SPAN paradigm in preclinical research.

A multi-laboratory preclinical trial in rodents to assess treatment candidates for acute ischemic stroke.

Human diseases may be modeled in animals to allow preclinical assessment of putative new clinical interventions. Recent, highly publicized failures of large clinical trials called into question the rigor, design, and value of preclinical assessment. We established the Stroke Preclinical Assessment Network (SPAN) to design and implement a randomized, controlled, blinded, multi-laboratory trial for the rigorous assessment of candidate stroke treatments combined with intravascular thrombectomy. Efficacy and futility boundaries in a multi-arm multi-stage statistical design aimed to exclude from further study highly effective or futile interventions after each of four sequential stages. Six independent research laboratories performed a standard focal cerebral ischemic insult in five animal models that included equal numbers of males and females: young mice, young rats, aging mice, mice with diet-induced obesity, and spontaneously hypertensive rats. The laboratories adhered to a common protocol and efficiently enrolled 2615 animals with full data completion and comprehensive animal tracking. SPAN successfully implemented treatment masking, randomization, prerandomization inclusion and exclusion criteria, and blinded assessment of outcomes. The SPAN design and infrastructure provide an effective approach that could be used in similar preclinical, multi-laboratory studies in other disease areas and should help improve reproducibility in translational science.

Targeting Neutrophil α9 Improves Functional Outcomes After Stroke in Mice With Obesity-Induced Hyperglycemia.

BACKGROUND: Obesity-induced hyperglycemia is a significant risk factor for stroke. Integrin α9ß1 is expressed on neutrophils and stabilizes adhesion to the endothelium via ligands, including Fn-EDA (fibronectin containing extra domain A) and tenascin C. Although myeloid deletion of α9 reduces susceptibility to ischemic stroke, it is unclear whether this is mediated by neutrophil-derived α9. We determined the role of neutrophil-specific α9 in stroke outcomes in a mice model with obesity-induced hyperglycemia. METHODS: α9Neu-KO (α9fl/flMRP8Cre+) and littermate control α9WT (α9fl/flMRP8Cre-) mice were fed on a 60% high-fat diet for 20 weeks to induce obesity-induced hyperglycemia. Functional outcomes were evaluated up to 28 days after stroke onset in mice of both sexes using a transient (30 minutes) middle cerebral artery ischemia. Infarct volume (magnetic resonance imaging) and postreperfusion thrombo-inflammation (thrombi, fibrin, neutrophil, phospho-nuclear factor kappa B [p-NFκB], TNF [tumor necrosis factor]-α, and IL [interleukin]-1ß levels, markers of neutrophil extracellular traps) were measured post 6 or 48 hours of reperfusion. In addition, functional outcomes (modified Neurological Severity Score, rota-rod, corner, and wire-hanging test) were measured for up to 4 weeks. RESULTS: Stroke upregulated neutrophil α9 expression more in obese mice (P<0.05 versus lean mice). Irrespective of sex, deletion of neutrophil α9 improved functional outcomes up to 4 weeks, concomitant with reduced infarct, improved cerebral blood flow, decreased postreperfusion thrombo-inflammation, and neutrophil extracellular traps formation (NETosis) (P<0.05 versus α9WT obese mice). Obese α9Neu-KO mice were less susceptible to thrombosis in FeCl3 injury-induced carotid thrombosis model. Mechanistically, we found that α9/cellular fibronectin axis contributes to NETosis via ERK (extracellular signal-regulated kinase) and PAD4 (peptidyl arginine deiminase 4), and neutrophil α9 worsens stroke outcomes via cellular fibronectin-EDA but not tenascin C. Obese wild-type mice infused with anti-integrin α9 exhibited improved functional outcomes up to 4 weeks (P<0.05 versus vehicle). CONCLUSIONS: Genetic ablation of neutrophil-specific α9 or pharmacological inhibition improves long-term functional outcomes after stroke in mice with obesity-induced hyperglycemia, most likely by limiting thrombo-inflammation.

In-hospital outcomes and recurrence of stroke during pregnancy and puerperium.

BACKGROUND: There are limited data regarding the best management and outcomes of acute stroke during pregnancy and the puerperium. METHODS: Pregnancy-related hospitalizations with age > 18 years were identified from the Nationwide Readmissions Database 2016-2018. The study cohort consisted of all patients with acute stroke and a 5% random sample of the remaining non-stroke hospitalizations. Logistic regression and survival analyses were used to compare the in-hospital outcomes and readmissions in patients with and without acute stroke. RESULTS: There were 11,829,044 pregnancy-related hospitalizations, of which 4057 had acute stroke. The mean ± SD age of the study cohort was 29.0 ± 5.7 years. Among patients with acute ischemic stroke, 60 (3.7%) patients received intravenous thrombolysis and 112 (6.8%) patients underwent endovascular thrombectomy. Among patients with intracranial hemorrhage, 205 (10.5%) patients underwent ventriculostomy and 18 (0.9%) patients underwent decompressive craniotomy. Patients with stroke had longer length of stay (mean: 10.7 vs 2.7 days), higher in-hospital mortality (4.6% vs 0.0001%) and were less likely to discharge home (73.0% vs 98.6%). Non-elective readmission within 90 days of discharge occurred in 14.8% of patients with stroke versus in 3.9% of patients without stroke. Readmissions due to cerebrovascular events occurred in 2.3% of patients with stroke versus in 0.007% of patients without stroke within 1 year of discharge, with mean ± SD time to readmission 66.2 ± 78.0 days. CONCLUSION: Stroke is a serious complication of pregnancy, associated with high morbidity and mortality. Recurrence of stroke occurs in a small proportion of patients, and the risk is highest during the initial 3 months.

High resolution 7T MR imaging in characterizing culprit intracranial atherosclerotic plaques.

BACKGROUND: Current imaging modalities underestimate the severity of intracranial atherosclerotic disease (ICAD). High resolution vessel wall imaging (HR-VWI) MRI is a powerful tool in characterizing plaques. We aim to show that HR-VWI MRI is more accurate at detecting and characterizing intracranial plaques compared to digital subtraction angiography (DSA), time-of-flight (TOF) MRA, and computed tomography angiogram (CTA). METHODS: Patients with symptomatic ICAD prospectively underwent 7T HR-VWI. We calculated: degree of stenosis, plaque burden (PB), and remodeling index (RI). The sensitivity of detecting a culprit plaque for each modality as well as the correlations between different variables were analyzed. Interobserver agreement on the determination of a culprit plaque on every imaging modality was evaluated. RESULTS: A total of 44 patients underwent HR-VWI. Thirty-four patients had CTA, 18 TOF-MRA, and 18 DSA. The sensitivity of plaque detection was 88% for DSA, 78% for TOF-MRA, and 76% for CTA. There's significant positive correlation between PB and degree of stenosis on HR-VWI MRI (p < 0.001), but not between PB and degree of stenosis in DSA (p = 0.168), TOF-MRA (p = 0.144), and CTA (p = 0.253). RI had a significant negative correlation with degree of stenosis on HR-VWI MRI (p = 0.003), but not on DSA (p = 0.783), TOF-MRA (p = 0.405), or CTA (p = 0.751). The best inter-rater agreement for culprit plaque detection was with HR-VWI (p = 0.001). CONCLUSIONS: The degree of stenosis measured by intra-luminal techniques does not fully reflect the true extent of ICAD. HR-VWI is a more accurate tool in characterizing atherosclerotic plaques and may be the default imaging modality in clinical practice.

The Stroke Preclinical Assessment Network: Rationale, Design, Feasibility, and Stage 1 Results.

Cerebral ischemia and reperfusion initiate cellular events in brain that lead to neurological disability. Investigating these cellular events provides ample targets for developing new treatments. Despite considerable work, no such therapy has translated into successful stroke treatment. Among other issues-such as incomplete mechanistic knowledge and faulty clinical trial design-a key contributor to prior translational failures may be insufficient scientific rigor during preclinical assessment: nonblinded outcome assessment; missing randomization; inappropriate sample sizes; and preclinical assessments in young male animals that ignore relevant biological variables, such as age, sex, and relevant comorbid diseases. Promising results are rarely replicated in multiple laboratories. We sought to address some of these issues with rigorous assessment of candidate treatments across 6 independent research laboratories. The Stroke Preclinical Assessment Network (SPAN) implements state-of-the-art experimental design to test the hypothesis that rigorous preclinical assessment can successfully reduce or eliminate common sources of bias in choosing treatments for evaluation in clinical studies. SPAN is a randomized, placebo-controlled, blinded, multilaboratory trial using a multi-arm multi-stage protocol to select one or more putative stroke treatments with an implied high likelihood of success in human clinical stroke trials. The first stage of SPAN implemented procedural standardization and experimental rigor. All participating research laboratories performed middle cerebral artery occlusion surgery adhering to a common protocol and rapidly enrolled 913 mice in the first of 4 planned stages with excellent protocol adherence, remarkable data completion and low rates of subject loss. SPAN stage 1 successfully implemented treatment masking, randomization, prerandomization inclusion/exclusion criteria, and blinded assessment to exclude bias. Our data suggest that a large, multilaboratory, preclinical assessment effort to reduce known sources of bias is feasible and practical. Subsequent SPAN stages will evaluate candidate treatments for potential success in future stroke clinical trials using aged animals and animals with comorbid conditions.

Self-controlled assessment of thromboembolic event (TEE) risk following intravenous immune globulin (IGIV) in the U.S. (2006-2012).

Since 2013, the U.S. Food and Drug administration (FDA) has required that intravenous immune globulin (IGIV) products carry a boxed warning concerning the risk of thromboembolic events (TEEs). This study assessed the incidence of TEEs attributable to IGIV in a large population-based cohort. A self-controlled risk interval design was used to quantify the transient increase in TEE risk during the risk interval (days 0-2 and 0-13 following IGIV for arterial and venous TEEs, respectively) relative to a later control interval (days 14-27 following IGIV). Potential IGIV-exposed TEE cases from 2006 to 2012 were identified from the FDA-sponsored Sentinel Distributed Database and confirmed through medical record review. Inpatient IGIV exposures were not included in the venous TEE analysis due to concerns about time-varying confounding. 19,069 new users of IGIV who received 93,555 treatment episodes were included. Charts were retrieved for 62% and 70% of potential venous and arterial cases, respectively. There was a transient increase in the risk of arterial TEEs during days 0-2 following IGIV treatment (RR = 4.69; 95% CI 1.87, 11.90; absolute increase in risk = 8.86 events per 10,000 patients, 95% CI 3.25, 14.6), but no significant increase in venous TEE risk during days 0-13 following outpatient IGIV treatments (RR = 1.07, 95% CI 0.34, 3.48). Our results suggest there is a small increase in the absolute risk of arterial TEEs following IGIV. However, lower-than-expected chart retrieval rates and the possibility of time-varying confounding mean that our results should be interpreted cautiously. Continued pharmacovigilance efforts are warranted.

PKM2 promotes neutrophil activation and cerebral thromboinflammation: therapeutic implications for ischemic stroke.

There is a critical need for cerebro-protective interventions to improve the suboptimal outcomes of patients with ischemic stroke who have been treated with reperfusion strategies. We found that nuclear pyruvate kinase muscle 2 (PKM2), a modulator of systemic inflammation, was upregulated in neutrophils after the onset of ischemic stroke in both humans and mice. Therefore, we determined the role of PKM2 in stroke pathogenesis by using murine models with preexisting comorbidities. We generated novel myeloid cell-specific PKM2-/- mice on wild-type (PKM2fl/flLysMCre+) and hyperlipidemic background (PKM2fl/flLysMCre+Apoe-/-). Controls were littermate PKM2fl/flLysMCre- or PKM2fl/flLysMCre-Apoe-/- mice. Genetic deletion of PKM2 in myeloid cells limited inflammatory response in peripheral neutrophils and reduced neutrophil extracellular traps after cerebral ischemia and reperfusion, suggesting that PKM2 promotes neutrophil hyperactivation in the setting of stroke. In the filament and autologous clot and recombinant tissue plasminogen activator stroke models, irrespective of sex, deletion of PKM2 in myeloid cells in either wild-type or hyperlipidemic mice reduced infarcts and enhanced long-term sensorimotor recovery. Laser speckle imaging revealed improved regional cerebral blood flow in myeloid cell-specific PKM2-deficient mice that was concomitant with reduced post-ischemic cerebral thrombo-inflammation (intracerebral fibrinogen, platelet [CD41+] deposition, neutrophil infiltration, and inflammatory cytokines). Mechanistically, PKM2 regulates post-ischemic inflammation in peripheral neutrophils by promoting STAT3 phosphorylation. To enhance the translational significance, we inhibited PKM2 nuclear translocation using a small molecule and found significantly reduced neutrophil hyperactivation and improved short-term and long-term functional outcomes after stroke. Collectively, these findings identify PKM2 as a novel therapeutic target to improve brain salvage and recovery after reperfusion.

Risk of Venous Thromboembolism in Hospitalized Patients with Acute Ischemic Stroke Versus Other Neurological Conditions.

BACKGROUND: The mechanism of increased risk of venous thromboembolism (VTE) after acute ischemic stroke (AIS) is unclear. In this study, we aimed to evaluate the risk of VTE in hospitalizations due to AIS as compared to those due to non-vascular neurological conditions. We also aimed to assess any potential association between VTE risk and the use of intravenous thrombolysis (rtPA) among hospitalizations with AIS. MATERIALS AND METHODS: In this case-control study, data were obtained from the Nationwide Inpatient Sample 2016-2018. Propensity score matching was used to adjust for the baseline differences between the groups. Logistic regression analysis was used to compare the risk of VTE. RESULTS: We identified 1,541,685 hospitalizations due to AIS and 1,453,520 hospitalizations due to non-vascular neurological diagnoses that served as controls. After propensity score matching, 640,560 cases with AIS and corresponding well-matched controls were obtained. Hospitalizations due to AIS had higher odds of VTE as compared to the controls [odds ratio (OR) 1.50, 95% confidence interval (CI) 1.40-1.60, P<0.001]. Among hospitalizations with AIS, 184,065 (11.9%) got rtPA. The odds of VTE were lower among the AIS hospitalizations that received rtPA as compared to those that did not (OR 0.89, 95% CI 0.79-0.99, P0.035). CONCLUSION: Hospitalizations due to AIS have a higher risk of VTE as compared to the non-vascular neurological controls. Among AIS cases, the risk of VTE is lower among patients treated with rtPA. These epidemiological findings support the hypothesis that the risk of VTE after AIS might be partly mediated by an intrinsic pro-coagulant state.

The Intracerebral Hemorrhage Score Overestimates Mortality in Young Adults.

OBJECTIVE: To determine whether the intracerebral hemorrhage (ICH) score is accurate in predicting 30-day mortality in young adults, we calculated the ICH score for 156 young adults (aged 18-45) with primary spontaneous ICH and compared predicted to observed 30-day mortality rates. METHODS: We retrospectively reviewed all patients aged 18-45 consecutively presenting to the University of Iowa from 2009 to 2019 with ICH. We calculated the ICH score and recorded its individual subcomponents for each patient. Poisson regression was used to test the association of ICH score components with 30-day mortality. RESULTS: We identified 156 patients who met the inclusion criteria; mean± standard deviation (SD) age was 35±8 years. The 30-day mortality rate was 15% (n=24). The ICH score was predictive of 30-day mortality for each unit increase (p= 0.04 for trend), but the observed mortality rates for each ICH score varied considerably from the original ICH score predictions. Most notably, the 30-day mortality rates for ICH scores of 1, 2, and 3 are predicted to be 13%, 26%, and 72% respectively, but were observed in our population to be 0%, 3%, and 41%. An ICH volume of >30cc [relative risk (RR) 28, 95% confidence intervals (CI) 3-315, p=0.01] and a GCS score of <5 (RR 13, 95% CI 0.1-1176, p=0.01) were independently associated with 30-day mortality. CONCLUSIONS: The ICH score tends to overestimate mortality in young adults. ICH volume and GCS score are the most relevant items in predicting mortality at 30 days in young adults.

Effects of the Menstrual Cycle on Neurological Disorders.

PURPOSE OF REVIEW: The menstrual cycle involves recurrent fluctuations in hormone levels and temperature via neuroendocrine feedback loops. This paper reviews the impact of the menstrual cycle on several common neurological conditions, including migraine, seizures, multiple sclerosis, stroke, and Parkinson's disease. RECENT FINDINGS: The ovarian steroid hormones, estrogen and progesterone, have protean effects on central nervous system functioning that can impact the likelihood, severity, and presentation of many neurological diseases. Hormonal therapies have been explored as a potential treatment for many neurological diseases with varying degrees of evidence and success. Neurological conditions also impact women's reproductive health, and the cessation of ovarian function with menopause may also alter the course of neurological diseases. Medication selection must consider hormonal effects on metabolism and the potential for adverse drug reactions related to menstruation, fertility, and pregnancy outcomes. Novel medications with selective affinity for hormonal receptors are desirable. Neurologists and gynecologists must collaborate to provide optimal care for women with neurological disorders.

Transient global amnesia does not increase the risk of subsequent ischemic stroke: a propensity score-matched analysis.

INTRODUCTION: Data regarding the risk of cerebrovascular events following transient global amnesia (TGA) remain controversial. While some neuroradiological studies suggest an underlying cerebrovascular etiology, results from the clinical studies have been largely conflicting. We, therefore, aimed to evaluate the risk of ischemic stroke in a large, nationally representative sample of patients with TGA. METHODS: We utilized the Nationwide Readmissions Database 2010-2015 to identify all hospitalizations with the primary discharge diagnosis of TGA. We selected a 2% random sample of all elective admissions to be included as controls. A propensity score-matched analysis was performed to match patients with TGA and the controls. The primary outcome was readmission due to ischemic stroke up to 1 year following discharge from the index hospitalization, assessed using the Kaplan-Meier survival analysis in the propensity-matched groups. RESULTS: There were 24,803 weighted hospitalizations due to TGA (mean ± SD age: 65.6 ± 10.4 years, female: 54.9%) and 699,644 corresponding controls. At baseline, patients with TGA were significantly older, more likely to be male, and had a higher prevalence of hypertension, hyperlipidemia, coronary artery disease, cerebrovascular disease, and migraine, as compared to the controls. However, after propensity score matching, we obtained 21,202 cases and 21,293 well-matched corresponding controls, and the risk of readmission due to ischemic stroke in patients with TGA was not different compared to the control group (HR: 1.13, 95% CI 0.62-2.05, P 0.686) during the mean (SD) follow-up period of 192.2 (102.4) days. CONCLUSIONS: After adjustment for demographics and cerebrovascular risk factors, TGA is not associated with an increased risk of subsequent ischemic stroke.

Neurologic complications of heart surgery.

Cardiac surgeries are commonly associated with neurologic complications. The type and complexity of the surgery, as well as patients' comorbidities, determine the risk for these complications. Awareness and swift recognition of these complications may have significant implications on management and prognosis. Recent trials resulted in an expansion of the time window to treat patients with acute ischemic stroke with intravenous thrombolysis and/or mechanical thrombectomy using advanced neuroimaging for screening. The expanded time window increases the reperfusion treatment options for patients that suffer a periprocedural ischemic stroke. Moreover, there is now limited data available to help guide management of intracerebral hemorrhage in patients undergoing treatment with anticoagulation for highly thrombogenic conditions, such as left ventricular assist devices and mechanical valves. In addition to cerebrovascular complications patients undergoing heart surgery are at increased risk for seizures, contrast toxicity, cognitive changes, psychological complications, and peripheral nerve injuries. We review the neurological complications associated with the most common cardiac surgeries and discuss clinical presentation, diagnosis and management strategies.

Impact of Intracerebral Hematoma Evacuation During Decompressive Hemicraniectomy on Functional Outcomes.

BACKGROUND AND PURPOSE: Decompressive hemicraniectomy has been used to treat spontaneous intracerebral hemorrhage, but the benefit of evacuating the hematoma during the procedure is unclear. We aim to evaluate the utility of performing clot evacuation during hemicraniectomy for spontaneous intracerebral hemorrhage. METHODS: Retrospective cohort of consecutive patients (2010-2019) treated with decompressive hemicraniectomy for a spontaneous supratentorial intracerebral hemorrhage at the University of Iowa. We compared hemicraniectomy alone to hemicraniectomy plus hematoma evacuation. We analyzed clinical features and hematoma characteristics. The outcomes at 6 months were dichotomized into unfavorable (Glasgow Outcome Scale score 1-3) and favorable (Glasgow Outcome Scale score 4-5). RESULTS: Eighty-three patients underwent decompressive hemicraniectomy for spontaneous intracerebral hemorrhage, 52 with hematoma evacuation, and 31 without hematoma evacuation. There were no statistically significant differences in clinical and radiographic characteristics between the 2 groups. Evacuating the hematoma in addition to hemicraniectomy did not change the odds of favorable outcome at 6 months (P=0.806). CONCLUSIONS: In this retrospective study, the performance of hematoma evacuation during decompressive hemicraniectomy for spontaneous intracerebral hemorrhage may not change functional outcomes over performing the hemicraniectomy alone.

Comparative Effectiveness and Safety of Direct Oral Anticoagulants in Obese Patients with Atrial Fibrillation.

BACKGROUND: Unlike warfarin direct oral anticoagulants (DOACs) are administered in fixed doses, which raises concerns of its effectiveness on larger patients. Data from randomized trials are limited on the safety and efficacy of DOACs in morbidly obese individuals with atrial fibrillation (AF). METHODS: We analyzed a cohort of obese (≥ 120 kg) and morbidly obese (BMI > 40 kg/m2) patients from the Veterans Health Administration system with AF who initiated apixaban, rivaroxaban, dabigatran, or warfarin between years 2012 and 2018. We used inverse probability of treatment weighting (IPTW) and Cox proportional hazards regression models to evaluate the relative hazard of death, myocardial infarction (MI), ischemic stroke, heart failure (HF), and bleeding events between oral anticoagulant (OAC) groups while censoring for medication cessation. RESULTS: We identified 6052 obese patients on apixaban, 4233 on dabigatran, 4309 on rivaroxaban, and 13,417 on warfarin (mean age 66.7 years, 91% males, 80.4% whites). At baseline patients on apixaban had the lowest glomerular filtration rate and highest rates of previous stroke and MI compared to other OACs. Among patients with weight ≥ 120 kg and those with BMI > 40 kg/m2, all DOACs were associated with lower risk of any hemorrhage, hemorrhagic stroke, and gastrointestinal (GI) bleeding. Patients with BMI > 40 kg/m2 treated with DOACs had similar ischemic stroke risk with those on warfarin. CONCLUSIONS: In this large cohort of obese Veterans Health Administration system patients, the use of DOACs resulted in lower hemorrhagic complications than warfarin while maintaining efficacy on ischemic stroke prevention.