Left Ventricular Dysfunction Among Patients With Embolic Stroke of Undetermined Source and the Effect of Rivaroxaban vs Aspirin: A Subgroup Analysis of the NAVIGATE ESUS Randomized Clinical Trial.

Importance: It is uncertain whether anticoagulation is superior to aspirin at reducing recurrent stroke in patients with recent embolic strokes of undetermined source (ESUS) and left ventricular (LV) dysfunction. Objective: To determine whether anticoagulation is superior to aspirin in reducing recurrent stroke in patients with ESUS and LV dysfunction. Design, Setting, and Participants: Post hoc exploratory analysis of data from the New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs Aspirin to Prevent Embolism in ESUS (NAVIGATE ESUS) trial, a randomized, phase 3 clinical trial with enrollment from December 2014 to September 2017. The study setting included 459 stroke recruitment centers in 31 countries. Patients 50 years or older who had neuroimaging-confirmed ESUS between 7 days and 6 months before screening were eligible. Of the 7213 NAVIGATE ESUS participants, 7107 (98.5%) had a documented assessment of LV function at study entry and were included in the present analysis. Data were analyzed in January 2021. Interventions: Participants were randomized to receive either 15 mg of rivaroxaban or 100 mg of aspirin once daily. Main Outcomes and Measures: The study examined whether rivaroxaban was superior to aspirin at reducing the risk of (1) the trial primary outcome of recurrent stroke or systemic embolism and (2) the trial secondary outcome of recurrent stroke, systemic embolism, myocardial infarction, or cardiovascular mortality during a median follow-up of 10.4 months. LV dysfunction was identified locally through echocardiography and defined as moderate to severe global impairment in LV contractility and/or a regional wall motion abnormality. A Cox proportional hazards model was used to assess for treatment interaction and to estimate the hazard ratios for those randomized to rivaroxaban vs aspirin by LV dysfunction status. Results: LV dysfunction was present in 502 participants (7.1%). Of participants with LV dysfunction, the mean (SD) age was 67 (10) years, and 130 (26%) were women. Among participants with LV dysfunction, annualized primary event rates were 2.4% (95% CI, 1.1-5.4) in those assigned to rivaroxaban vs 6.5% (95% CI, 4.0-11.0) in those assigned aspirin. Among the 6605 participants without LV dysfunction, rates were similar between those assigned to rivaroxaban (5.3%; 95% CI, 4.5-6.2) vs aspirin (4.5%; 95% CI, 3.8-5.3). Participants with LV dysfunction assigned to rivaroxaban vs aspirin had a lower risk of the primary outcome (hazard ratio, 0.36; 95% CI, 0.14-0.93), unlike those without LV dysfunction (hazard ratio, 1.16; 95% CI, 0.93-1.46) (P for treatment interaction = .03). Results were similar for the secondary outcome. Conclusions and Relevance: In this post hoc exploratory analysis, rivaroxaban was superior to aspirin in reducing the risk of recurrent stroke or systemic embolism among NAVIGATE ESUS participants with LV dysfunction. Trial Registration: ClinicalTrials.gov Identifier: NCT02313909.

Anti-edema and antioxidant combination therapy for ischemic stroke via glyburide-loaded betulinic acid nanoparticles.

Stroke is a deadly disease without effective pharmacotherapies, which is due to two major reasons. First, most therapeutics cannot efficiently penetrate the brain. Second, single agent pharmacotherapy may be insufficient and effective treatment of stroke requires targeting multiple complementary targets. Here, we set to develop single component, multifunctional nanoparticles (NPs) for targeted delivery of glyburide to the brain for stroke treatment. Methods: To characterize the brain penetrability, we radiolabeled glyburide, intravenously administered it to stroke- bearing mice, and determined its accumulation in the brain using positron emission tomography-computed tomography (PET/CT). To identify functional nanomaterials to improve drug delivery to the brain, we developed a chemical extraction approach and tested it for isolation of nanomaterials from E. ulmoides, a medicinal herb. To assess the therapeutic benefits, we synthesized glyburide-loaded NPs and evaluated them in stroke- bearing mice. Results: We found that glyburide has a limited ability to penetrate the ischemic brain. We identified betulinic acid (BA) capable of forming NPs, which, after intravenous administration, efficiently penetrate the brain and significantly reduce ischemia-induced infarction as an antioxidant agent. We demonstrated that BA NPs enhance delivery of glyburide, leading to therapeutic benefits significantly greater than those achieved by either glyburide or BA NPs. Conclusion: This study suggests a new direction to identify functional nanomaterials and a simple approach to achieving anti-edema and antioxidant combination therapy. The resulting glyburide- loaded BA NPs may be translated into clinical applications to improve clinical management of stroke.

A Qualitative Study of Risks Related to Interhospital Transfer of Patients with Nontraumatic Intracranial Hemorrhage.

GOAL: Interhospital transfer (IHT) facilitates access to specialized neurocritical care but may also introduce unique risk. Our goal was to describe providers' perceptions of safety threats during IHT for patients with nontraumatic intracranial hemorrhage. MATERIALS AND METHODS: We employed qualitative, semi-structured interviews at an academic medical center receiving critically-ill neurologic transfers, and 5 referring hospitals. Interviewees included physicians, nurses, and allied health professionals with experience caring for patients transferred between hospitals for nontraumatic intracranial hemorrhage. Interviews continued until data saturation was reached. Coding occurred concurrently with interviews. Analysis was inductive, using the constant comparative method. FINDINGS: The predominant impediments to safe, high-quality neurocritical care transitions between hospitals are insufficient communication, gaps in clinical practice, and lack of IHT structure. Insufficient communication highlights the unique communication challenges specific to IHT, which overlay and compound known intrahospital communication barriers. Gaps in clinical practice revolve primarily around the provision of neurocritical care for this patient population, often subject to resource availability, by receiving hospital emergency medicine providers. Lack of structure outlines providers' questions that emerge when institutions fail to identify process channels, expectations, and accountability during complex neurocritical care transitions. CONCLUSIONS: The predominant impediments to safe, high-quality neurocritical care transitions between hospitals are insufficient communication, gaps in clinical practice, and lack of IHT structure. These themes serve as fundamental targets for quality improvement initiatives. To our knowledge, this is the first description of challenges to quality and safety in high-risk neurocritical care transitions through clinicians' voices.

Trends in Interhospital Transfers and Mechanical Thrombectomy for United States Acute Ischemic Stroke Inpatients.

OBJECTIVE: Stroke care in the US is increasingly regionalized. Many patients undergo interhospital transfer to access specialized, time-sensitive interventions such as mechanical thrombectomy. METHODS: Using a stratified survey design of the US Nationwide Inpatient Sample (2009-2014) we examined trends in interhospital transfers for ischemic stroke resulting in mechanical thrombectomy. International Classification of Disease-Ninth Revision (ICD-9) codes were used to identify stroke admissions and inpatient procedures within endovascular-capable hospitals. Regression analysis was used to identify factors associated with patient outcomes. RESULTS: From 2009-2014, 772,437 ischemic stroke admissions were identified. Stroke admissions that arrived via interhospital transfer increased from 12.5% to 16.8%, 2009-2014 (P-trend < .001). Transfers receiving thrombectomy increased from 4.0% to 5.2%, 2009-2014 (P-trend = .016), while those receiving tissue plasminogen activator increased from 16.0% to 20.0%, 2009-2014 (P-trend < .001). One in 4 patients receiving thrombectomy were transferred from another acute care facility (n = 6,014 of 24,861). Compared to patients arriving via the hospital "front door" receiving mechanical thrombectomy, those arriving via transfer were more often from rural areas and received by teaching hospitals with greater frequency of thrombectomy. Those arriving via interhospital transfer undergoing thrombectomy had greater odds of symptomatic intracranial hemorrhage (adjusted odds ratio [AOR] 1.19, 95% CI: 1.01-1.42) versus "front door" arrivals. There were no differences in inpatient mortality (AOR 1.11, 95% CI: .93-1.33). CONCLUSIONS: From 2009 to 2014, interhospital stroke transfers to endovascular-capable hospitals increased by one-third. For every ∼15 additional transfers over the time period one additional patient received thrombectomy. Optimization of transfers presents an opportunity to increase access to thrombectomy.

The American Heart Association's Get With the Guidelines (GWTG)-Stroke development and impact on stroke care.

The American Heart Association's Get With the Guidelines (GWTG)-Stroke programme has changed stroke care delivery in the USA since its establishment in 2003. GWTG is a voluntary registry and continuous quality improvement initiative that collects data on patient characteristics, hospital adherence to guidelines and inpatient outcomes. Implementation of the programme saw increased provision of evidence-based care and improved patient outcomes. This review will describe the development of the programme and discuss the impact on stroke outcomes and transformation of stroke care delivery that followed its implementation.

Selective Sphingosine-1-Phosphate Receptor 1 Modulation Attenuates Experimental Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Preclinical studies and a proof-of-concept clinical study have shown that sphingosine-1-phosphate receptor (S1PR) modulator, fingolimod, improves the clinical outcome of intracerebral hemorrhage (ICH). However, the specific subtype of the S1PRs through which immune modulation provides protection in ICH remains unclear. In addition, fingolimod-induced adverse effects could limit its use in patients with stroke because of interactions with other S1PR subtypes, particularly with S1PR3. RP101075 is a selective S1PR1 agonist with superior cardiovascular safety profile. In this study, we investigated the impact of RP101075 treatment in a mouse model of ICH. METHODS: ICH was induced by injection of autologous blood in 294 male C57BL/6J and Rag2(-/-) mice. ICH mice randomly received vehicle, RP101075, or RP101075 plus S1PR1 antagonist W146 by daily oral gavage for three consecutive days, starting from 30 minutes after surgery. Neurodeficits, brain edema, brain infiltration of immune cells, blood-brain barrier integrity, and cell death were assessed after ICH. RESULTS: RP101075 significantly attenuated neurological deficits and reduced brain edema in ICH mice. W146 blocked the effects of RP101075 on neurodeficits and brain edema. RP101075 reduced the counts of brain-infiltrating lymphocytes, neutrophils, and microglia, as well as cytokine expression after ICH. Enhanced blood-brain barrier integrity and alleviated neuronal death were also seen in ICH mice after RP101075 treatment. CONCLUSIONS: S1PR1 modulation via RP101075 provides protection in experimental ICH. Together with the advantageous pharmacological features of RP101075, these results warrant further investigations of its mechanisms of action and translational values in ICH patients.