Materials Characterization of Stereolithography 3D Printed Polymer to Develop a Self-Driven Microfluidic Device for Bioanalytical Applications.

Stereolithography (SLA) 3D printing is a rapid prototyping technique and reproducible manufacturing platform, which makes it a useful tool to develop advanced microfluidic devices for bioanalytical applications. However, limited information exists regarding the physical, chemical, and biological properties of the photocured polymers printed with SLA. This study demonstrates the characterization of a commercially available SLA 3D printed polymer to evaluate the potential presence of any time-dependent changes in material properties that may affect its ability to produce functional, capillary-action microfluidic devices. The printed polymer was analyzed with Fourier transform infrared-attenuated total reflectance, contact angle measurements, tensile test, impact test, scanning electron microscopy, and fluid flow analysis. Polymer biocompatibility was assessed with propidium iodide flow cytometry and an MTT assay for cell viability. The material characterization and biocompatibility results were then implemented to design and fabricate a self-driven capillary action microfluidic device for future use as a bioanalytical assay. This study demonstrates temporally stable mechanical properties and biocompatibility of the SLA polymer. However, surface characterization through contact angle measurements shows the polymer's wettability changes over time which indicates there is a limited postprinting period when the polymer can be used for capillary-based fluid flow. Overall, this study demonstrates the feasibility of implementing SLA as a high-throughput manufacturing method for capillary action microfluidic devices.

Differentiation of Pluripotent Stem Cells for Disease Modeling: Learning from Heart Development.

Heart disease is a pressing public health problem and the leading cause of death worldwide. The heart is the first organ to gain function during embryogenesis in mammals. Heart development involves cell determination, expansion, migration, and crosstalk, which are orchestrated by numerous signaling pathways, such as the Wnt, TGF-ß, IGF, and Retinoic acid signaling pathways. Human-induced pluripotent stem cell-based platforms are emerging as promising approaches for modeling heart disease in vitro. Understanding the signaling pathways that are essential for cardiac development has shed light on the molecular mechanisms of congenital heart defects and postnatal heart diseases, significantly advancing stem cell-based platforms to model heart diseases. This review summarizes signaling pathways that are crucial for heart development and discusses how these findings improve the strategies for modeling human heart disease in vitro.

Advances in the Generation of Constructed Cardiac Tissue Derived from Induced Pluripotent Stem Cells for Disease Modeling and Therapeutic Discovery.

The human heart lacks significant regenerative capacity; thus, the solution to heart failure (HF) remains organ donation, requiring surgery and immunosuppression. The demand for constructed cardiac tissues (CCTs) to model and treat disease continues to grow. Recent advances in induced pluripotent stem cell (iPSC) manipulation, CRISPR gene editing, and 3D tissue culture have enabled a boom in iPSC-derived CCTs (iPSC-CCTs) with diverse cell types and architecture. Compared with 2D-cultured cells, iPSC-CCTs better recapitulate heart biology, demonstrating the potential to advance organ modeling, drug discovery, and regenerative medicine, though iPSC-CCTs could benefit from better methods to faithfully mimic heart physiology and electrophysiology. Here, we summarize advances in iPSC-CCTs and future developments in the vascularization, immunization, and maturation of iPSC-CCTs for study and therapy.

Definition of factor Xa inhibitor-related, life-threatening gastrointestinal bleeding and guidance on when to use reversal therapy: A Delphi panel.

Objective: To define and contextualize life-threatening gastrointestinal (GI) bleeding in the setting of factor Xa (FXa) inhibitor therapy and to derive a consensus-based, clinically oriented approach to the administration of FXa inhibitor reversal therapy. Methods: We convened an expert panel of clinicians representing specialties in emergency medicine, gastroenterology, vascular medicine, and trauma surgery. Consensus was reached among the clinician panelists using the Delphi technique, which consisted of 2 survey questionnaires followed by virtual, real-time consensus-building exercises. Results: Hypovolemia and hemodynamic instability were considered the most important clinical signs of FXa inhibitor-related, life-threatening GI bleeds. Clinician panelists agreed that potentially life-threatening GI bleeding should be determined on the basis of hemodynamic instability, signs of shock, individual patient characteristics, and clinical judgment. Last, the panel agreed that all patients with life-threatening, FXa inhibitor-associated GI bleeding should be considered for FXa inhibitor reversal therapy; the decision to reverse FXa inhibition should be individualized, weighing the risks and benefits of reversal; and when reversal is elected, therapy should be administered within 1 h after initial emergency department evaluation, when possible. Conclusions: Consensus-based definitions of life-threatening GI bleeding and approaches to FXa inhibitor reversal centered on hemodynamic instability, signs of shock, individual patient characteristics, and clinical judgment. The results from this Delphi panel may inform clinical decision-making for the treatment of patients experiencing GI bleeding associated with FXa inhibitor use in the emergency department setting.

Development of a Resilience Parameter for 3D-Printable Shape Memory Polymer Blends.

The goal of this paper was to establish a metric, which we refer to as the resilience parameter, to evaluate the ability of a material to retain tensile strength after damage recovery for shape memory polymer (SMP) systems. In this work, three SMP blends created for the additive manufacturing process of fused filament fabrication (FFF) were characterized. The three polymer systems examined in this study were 50/50 by weight binary blends of the following constituents: (1) polylactic acid (PLA) and maleated styrene-ethylene-butylene-styrene (SEBS-g-MA); (2) acrylonitrile butadiene styrene (ABS) and SEBS-g-MA); and (3) PLA and thermoplastic polyurethane (TPU). The blends were melt compounded and specimens were fabricated by way of FFF and injection molding (IM). The effect of shape memory recovery from varying amounts of initial tensile deformation on the mechanical properties of each blend, in both additively manufactured and injection molded forms, was characterized in terms of the change in tensile strength vs. the amount of deformation the specimens recovered from. The findings of this research indicated a sensitivity to manufacturing method for the PLA/TPU blend, which showed an increase in strength with increasing deformation recovery for the injection molded samples, which indicates this blend had excellent resilience. The ABS/SEBS blend showed no change in strength with the amount of deformation recovery, indicating that this blend had good resilience. The PLA/SEBS showed a decrease in strength with an increasing amount of initial deformation, indicating that this blend had poor resilience. The premise behind the development of this parameter is to promote and aid the notion that increased use of shape memory and self-healing polymers could be a strategy for mitigating plastic waste in the environment.

Isoelectric point (pI)-based phase separation (pI-BPS) purification of elastin-like polypeptides (ELPs) containing charged, biologically active fusion proteins (ELP-FPs).

Elastin-like polypeptides (ELPs) are peptide-based biomaterials with residue sequence (VPGXG)n where X is any residue except proline. ELPs are a useful modality for delivering biologically active proteins (growth factors, protease inhibitors, anti-inflammatory peptides, etc.) as fusion proteins (ELP-FP). ELP-FPs are particularly cost-effective because they can be rapidly purified using Inverse Temperature Cycling (ITC) via the reversible formation and precipitation of entropically driven aggregates above a transition temperature (Tt ). When ELP fusion proteins (ELP-FPs) contain significant charge density at physiological pH, electrostatic repulsion between them severely inhibits aggregate formation. The literature does not currently describe methods for purifying ELP-FPs containing charged proteins on either side of the ELP sequence as fusion partners without organic solvents. Here, the isoelectric point (pI) of ELP-FPs is discussed as a means of neutralizing surface charges on ELP-FPs and increasing ITC yield to dramatically high levels. We use pI-based phase separation (pI-BPS) to purify ELP-FPs containing cationic and anionic fusion proteins. We report a dramatic increase in protein yield when using pI-BPS for purification of ELP-FPs. Proteins purified by this method also retain the functional activity of the protein present in the ELP-FP. Techniques developed here enable significant diversification of possible fusion proteins delivered by ELPs as ELP-FPs by allowing them to be produced and purified at higher quantities and yields.

Retrospective Analysis of the Real-World Utilization of 4-Factor Prothrombin Complex Concentrate and Plasma in Oral Anticoagulant-Associated Bleeding in US Hospitals.

Real-world utilization of 4-factor prothrombin complex concentrate (4F-PCC) and plasma for the management of oral anticoagulant (OAC)-associated bleeding in US trauma hospitals was described.This is amulticenter, retrospective chart review evaluating the use of 4F-PCC and plasma in OAC reversal across medical specialties. Physicians completed a survey and extracted data from 3 to 5 patient charts. Variables of interest included medical specialty, urgency, and bleed type. Two hundred and thirty-five physicians completed the survey, and 861 patient charts were included in the study. 4F-PCC was commonly used in life-threatening or emergent indications, whereas plasma was used in emergent and urgent indications. Plasma was used mostly for patients on warfarin (53% vs 47% 4F-PCC) and 4F-PCC for those on apixaban (82% vs 18% plasma) and rivaroxaban (77% vs 23% plasma). This retrospective analysis showed that 4F-PCC was predominantly used for OAC reversal despite available specific reversal agents for some of the OAC. Although it is not recommended by any reversal guidelines, plasma is still used for OAC reversal. Plasma should be avoided in the management of OAC-associated bleeding.

Final Study Report of Andexanet Alfa for Major Bleeding With Factor Xa Inhibitors.

BACKGROUND: Andexanet alfa is a modified recombinant inactive factor Xa (FXa) designed to reverse FXa inhibitors. ANNEXA-4 (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors) was a multicenter, prospective, phase-3b/4, single-group cohort study that evaluated andexanet alfa in patients with acute major bleeding. The results of the final analyses are presented. METHODS: Patients with acute major bleeding within 18 hours of FXa inhibitor administration were enrolled. Co-primary end points were anti-FXa activity change from baseline during andexanet alfa treatment and excellent or good hemostatic efficacy, defined by a scale used in previous reversal studies, at 12 hours. The efficacy population included patients with baseline anti-FXa activity levels above predefined thresholds (≥75 ng/mL for apixaban and rivaroxaban, ≥40 ng/mL for edoxaban, and ≥0.25 IU/mL for enoxaparin; reported in the same units used for calibrators) who were adjudicated as meeting major bleeding criteria (modified International Society on Thrombosis and Haemostasis definition). The safety population included all patients. Major bleeding criteria, hemostatic efficacy, thrombotic events (stratified by occurring before or after restart of either prophylactic [ie, a lower dose, for prevention rather than treatment] or full-dose oral anticoagulation), and deaths were assessed by an independent adjudication committee. Median endogenous thrombin potential at baseline and across the follow-up period was a secondary outcome. RESULTS: There were 479 patients enrolled (mean age, 78 years; 54% male; 86% White); 81% were anticoagulated for atrial fibrillation, and the median time was 11.4 hours since last dose, with 245 (51%) on apixaban, 176 (37%) on rivaroxaban, 36 (8%) on edoxaban, and 22 (5%) on enoxaparin. Bleeding was predominantly intracranial (n=331 [69%]) or gastrointestinal (n=109 [23%]). In evaluable apixaban patients (n=172), median anti-FXa activity decreased from 146.9 ng/mL to 10.0 ng/mL (reduction, 93% [95% CI, 94-93]); in rivaroxaban patients (n=132), it decreased from 214.6 ng/mL to 10.8 ng/mL (94% [95% CI, 95-93]); in edoxaban patients (n=28), it decreased from 121.1 ng/mL to 24.4 ng/mL (71% [95% CI, 82-65); and in enoxaparin patients (n=17), it decreased from 0.48 IU/mL to 0.11 IU/mL (75% [95% CI, 79-67]). Excellent or good hemostasis occurred in 274 of 342 evaluable patients (80% [95% CI, 75-84]). In the safety population, thrombotic events occurred in 50 (10%) patients; in 16 patients, these occurred during treatment with prophylactic anticoagulation that began after the bleeding event. No thrombotic episodes occurred after oral anticoagulation restart. Specific to certain populations, reduction of anti-FXa activity from baseline to nadir significantly predicted hemostatic efficacy in patients with intracranial hemorrhage (area under the receiver operating characteristic curve, 0.62 [95% CI, 0.54-0.70]) and correlated with lower mortality in patients <75 years of age (adjusted P=0.022; unadjusted P=0.003). Median endogenous thrombin potential was within the normal range by the end of andexanet alfa bolus through 24 hours for all FXa inhibitors. CONCLUSIONS: In patients with major bleeding associated with the use of FXa inhibitors, treatment with andexanet alfa reduced anti-FXa activity and was associated with good or excellent hemostatic efficacy in 80% of patients. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02329327.

Smartphone imaging repository: a novel method for creating a CT image bank.

BACKGROUND: Imaging repositories are commonly attached to ongoing clinical trials, but capturing, transmitting, and storing images can be complicated and labor-intensive. Typical methods include outdated technologies such as compact discs. Electronic file transfer is becoming more common, but even this requires hours of staff time on dedicated computers in the radiology department. METHODS: We describe and test an image capture method using smartphone camera video-derived images of brain computed tomography (CT) scans of traumatic intracranial hemorrhage. The deidentified videos are emailed or uploaded from the emergency department for central adjudication. We selected eight scans, mild moderate, and severe subdural and multicompartmental hematomas and mild and moderate intraparenchymal hematomas. Ten users acquired data using seven different smartphones. We measured the time in seconds it took to capture and send the files. The primary outcomes were hematoma volume measured by ABC/2, Marshall scale, midline shift measurement, image quality by a contrast-to-noise ratio (CNR), and time to capture. A radiologist and an imaging scientist applied the ABC/2 method and calculated the Marshall scale and midline shift on the data acquired on different smartphones and the PACS in a randomized order. We calculate the intraclass correlation coefficient (ICC). We measured image quality by calculating the contrast-to-noise ratio (CNR). We report summary statistics on time to capture in the smartphone group without a comparator. RESULTS: ICC for lesion volume, midline shift, and Marshall score were 0.973 (95% CI 0.931, 0.994), 0.998 (95% CI: 0.996, 0.999), and 0.973 (0.931, 0.994), respectively. Lesion conspicuity was not different among the image types via assessment of CNR using the Friedman test, [Formula: see text] of 24.8, P = < .001, with a small Kendall's W effect size (0.591). Mean (standard deviation) time to capture and email the video was 60.1 (24.3) s. CONCLUSIONS: Typical smartphones may produce video image quality high enough for use in a clinical trial imaging repository. Video capture and transfer takes only seconds, and hematoma volumes, Marshall scales, and image quality measured on the videos did not differ significantly from those calculated on the PACS.

INR and vitamin K-dependent factor levels after vitamin K antagonist reversal with 4F-PCC or plasma.

Restoration of the international normalized ratio (INR) to values <1.5 is commonly targeted to achieve hemostasis in patients with major bleeding or undergoing urgent surgery who are treated using vitamin K antagonists (VKAs). However, the relationship between corrected INR and vitamin K-dependent factor (VKDF) levels for hemostasis is uncertain. We aim to examine the impact of 4-factor prothrombin complex concentrate (4F-PCC) or plasma on INR correction and VKDF restoration and evaluate the relationship between INR values and VKDF levels in patients with acute major bleeding or patients requiring an urgent surgical procedure. Adult patients treated with VKA with an elevated INR (≥2.0 within 3 hours before study treatment) who received 4F-PCC or plasma after major bleeding or before an urgent surgery or invasive procedure were included in this retrospective analysis of data from 2 prospective phase 3b randomized controlled trials. Of the 370 patients included in this analysis, 185 received 4F-PCC, and 185 received plasma. In the 4F-PCC group, 159 of 185 (85.9%) had an INR ≤1.5 at 30 minutes after the end of infusion compared with only 72 of 184 (39.1%) in the plasma group. After 4F-PCC treatment, all VKDF levels exceeded 50% activity regardless of the postinfusion INR value. However, after plasma administration, mean activity levels for factors II and X were <50% at all time points assessed within 3 hours after starting the infusion, regardless of the postinfusion INR value. This retrospective analysis demonstrated that treatment with 4F-PCC among patients treated with VKA rapidly restores VKDFs to hemostatic levels irrespective of the postinfusion INR value, whereas treatment with plasma does not.

Prospective Observational Cohort Study of Tenecteplase Versus Alteplase in Routine Clinical Practice.

BACKGROUND: A 10-hospital regional network transitioned to tenecteplase as the standard of care stroke thrombolytic in September 2019 because of potential workflow advantages and reported noninferior clinical outcomes relative to alteplase in meta-analyses of randomized trials. We assessed whether tenecteplase use in routine clinical practice reduced thrombolytic workflow times with noninferior clinical outcomes. METHODS: We designed a prospective registry-based observational, sequential cohort comparison of tenecteplase- (n=234) to alteplase-treated (n=354) stroke patients. We hypothesized: (1) an increase in the proportion of patients meeting target times for target door-to-needle time and transfer door-in-door-out time, and (2) noninferior favorable (discharge to home with independent ambulation) and unfavorable (symptomatic intracranial hemorrhage, in-hospital mortality or discharge to hospice) in the tenecteplase group. Total hospital cost associated with each treatment was also compared. RESULTS: Target door-to-needle time within 45 minutes for all patients was superior for tenecteplase, 41% versus 29%; adjusted odds ratio, 1.85 (95% CI, 1.27-2.71); P=0.001; 58% versus 41% by Get With The Guidelines criteria. Target door-in-door-out time within 90 minutes was superior for tenecteplase 37% (15/43) versus 14% (9/65); adjusted odds ratio, 3.62 (95% CI, 1.30-10.74); P=0.02. Favorable outcome for tenecteplase fell within the 6.5% noninferiority margin; adjusted odds ratio, 1.26 (95% CI, 0.89-1.80). Unfavorable outcome was less for tenecteplase, 7.3% versus 11.9%, adjusted odds ratio, 0.77 (95% CI, 0.42-1.37) but did not fall within the prespecified 1% noninferior boundary. Net benefit (%favorable-%unfavorable) was greater for the tenecteplase sample: 37% versus 27%. P=0.02. Median cost per hospital encounter was less for tenecteplase cases ($13 382 versus $15 841; P<0.001). CONCLUSIONS: Switching to tenecteplase in routine clinical practice in a 10-hospital network was associated with shorter door-to-needle time and door-in-door-out times, noninferior favorable clinical outcomes at discharge, and reduced hospital costs. Evaluation in larger, multicenter cohorts is recommended to determine if these observations generalize.

Use of deep artificial neural networks to identify stroke during triage via subtle changes in circulating cell counts.

BACKGROUND: The development of tools that could help emergency department clinicians recognize stroke during triage could reduce treatment delays and improve patient outcomes. Growing evidence suggests that stroke is associated with several changes in circulating cell counts. The aim of this study was to determine whether machine-learning can be used to identify stroke in the emergency department using data available from a routine complete blood count with differential. METHODS: Red blood cell, platelet, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts were assessed in admission blood samples collected from 160 stroke patients and 116 stroke mimics recruited from three geographically distinct clinical sites, and an ensemble artificial neural network model was developed and tested for its ability to discriminate between groups. RESULTS: Several modest but statistically significant differences were observed in cell counts between stroke patients and stroke mimics. The counts of no single cell population alone were adequate to discriminate between groups with high levels of accuracy; however, combined classification using the neural network model resulted in a dramatic and statistically significant improvement in diagnostic performance according to receiver-operating characteristic analysis. Furthermore, the neural network model displayed superior performance as a triage decision making tool compared to symptom-based tools such as the Cincinnati Prehospital Stroke Scale (CPSS) and the National Institutes of Health Stroke Scale (NIHSS) when assessed using decision curve analysis. CONCLUSIONS: Our results suggest that algorithmic analysis of commonly collected hematology data using machine-learning could potentially be used to help emergency department clinicians make better-informed triage decisions in situations where advanced imaging techniques or neurological expertise are not immediately available, or even to electronically flag patients in which stroke should be considered as a diagnosis as part of an automated stroke alert system.

Andexanet Alfa for Specific Anticoagulation Reversal in Patients with Acute Bleeding during Treatment with Edoxaban.

BACKGROUND: Andexanet alfa (andexanet) is approved for specific anticoagulation reversal in patients with life-threatening or uncontrolled bleeding during treatment with rivaroxaban or apixaban. There is limited experience with andexanet in patients with acute bleeding on edoxaban. METHODS: Patients with acute major bleeding within 18 hours of edoxaban intake were prospectively enrolled. Patients received a bolus and 2-hour follow-on infusion of andexanet. The co-primary efficacy outcomes were change in antifactor Xa activity and the percentage of patients achieving excellent or good hemostasis, 12 hours after andexanet treatment. Efficacy was analyzed in patients with confirmed major bleeding and baseline antifactor Xa activity ≥40 ng/mL. Safety was analyzed in all patients. RESULTS: Thirty-six patients (mean age: 82 years, 61.1% male and 91.7% with atrial fibrillation) with acute major bleeding on edoxaban received andexanet. The primary site of bleeding was intracranial in 29 patients (80.6%). In the efficacy population (n = 28), median antifactor Xa activity decreased from 121.1 (interquartile range [IQR]: 70.3-202.4) ng/mL at baseline to 24.0 (IQR: 77.7-83.7) ng/mL at the end of andexanet bolus (median decrease: 68.9%, 95% confidence interval [CI]: 56.1-77.7%). Excellent or good hemostasis at 12 hours was achieved in 78.6% (95% CI: 59.0-91.7%) of patients. Within 30 days, four patients (11.1%) experienced a thrombotic event and four others (11.1%) died. CONCLUSION: In patients with acute major bleeding on edoxaban, andexanet significantly decreased antifactor Xa activity. Hemostatic efficacy was similar to that observed in patients with bleeding on rivaroxaban or apixaban. Thrombotic events occurred at a rate expected in such patients.

Design of Shape Memory Thermoplastic Material Systems for FDM-Type Additive Manufacturing.

The work presented here describes a paradigm for the design of materials for additive manufacturing platforms based on taking advantage of unique physical properties imparted upon the material by the fabrication process. We sought to further investigate past work with binary shape memory polymer blends, which indicated that phase texturization caused by the fused filament fabrication (FFF) process enhanced shape memory properties. In this work, two multi-constituent shape memory polymer systems were developed where the miscibility parameter was the guide in material selection. A comparison with injection molded specimens was also carried out to further investigate the ability of the FFF process to enable enhanced shape memory characteristics as compared to other manufacturing methods. It was found that blend combinations with more closely matching miscibility parameters were more apt at yielding reliable shape memory polymer systems. However, when miscibility parameters differed, a pathway towards the creation of shape memory polymer systems capable of maintaining more than one temporary shape at a time was potentially realized. Additional aspects related to impact modifying of rigid thermoplastics as well as thermomechanical processing on induced crystallinity are also explored. Overall, this work serves as another example in the advancement of additive manufacturing via materials development.

Cardiovascular, Cellular, and Neural Adaptations to Hot Yoga versus Normal-Temperature Yoga.

CONTEXT: Chronic heat exposure promotes cardiovascular and cellular adaptations, improving an organism's ability to tolerate subsequent stressors. Heat exposure may also promote neural adaptations and alter the neural-hormonal stress response. Hot-temperature yoga (HY) combines mind-body exercise with heat exposure. The added heat component in HY may induce cardiovascular and cellular changes, along with neural benefits and modulation of stress hormones. AIMS: The purpose of the present study is to compare the cardiovascular, cellular heat shock protein 70 (HSP70), neural, and hormonal adaptations of HY versus normal-temperature yoga (NY). SETTINGS AND DESIGN: Twenty-two subjects (males = 11 and females = 11, 26 ± 6 years) completed 4 weeks of NY (n = 11) or HY (n = 11, 41°C, 40% humidity). Yoga sessions were performed 3 times/week following a modified Bikram protocol. SUBJECTS AND METHODS: Pre- and posttesting included (1) hemodynamic measures during a heat tolerance test and maximal aerobic fitness test; (2) neural and hormonal adaptations using serum brain-derived neurotrophic factor (BDNF) and adrenocorticotropic hormone (ACTH), along with a mental stress questionnaire; and (3) cellular adaptations (HSP70) in peripheral blood mononuclear cells (PBMCs). STATISTICAL ANALYSIS: Within- and between-group Student's t-test analyses were conducted to compare pre- and post-VO2 max, perceived stress, BDNF, HSP70, and ACTH in HY and NY groups. RESULTS: Maximal aerobic fitness increased in the HY group only. No evidence of heat acclimation or change in mental stress was observed. Serum BDNF significantly increased in yoga groups combined. Analysis of HSP70 suggested higher expression of HSP70 in the HY group only. CONCLUSIONS: Twelve sessions of HY promoted cardiovascular fitness and cellular thermotolerance adaptations. Serum BDNF increased in response to yoga (NY + HY) and appeared to not be temperature dependent.

Hemostatic Efficacy and Anti-FXa (Factor Xa) Reversal With Andexanet Alfa in Intracranial Hemorrhage: ANNEXA-4 Substudy.

Background and Purpose: Andexanet alfa is a recombinant modified human FXa (factor Xa) developed to reverse FXa inhibition from anticoagulants. Hemostatic efficacy and reversal of anti-FXa activity with andexanet were assessed in patients from the ANNEXA-4 study (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXa Inhibitors) with intracranial hemorrhage (ICrH). Methods: ANNEXA-4 was a single-arm study evaluating andexanet in patients presenting with major bleeding ≤18 hours after taking an FXa inhibitor. Patients received a bolus plus 2-hour infusion of andexanet. Brain imaging in patients with ICrH was performed at baseline and at 1 and 12 hours postandexanet infusion. Coprimary efficacy outcomes were change in anti-FXa activity and hemostatic efficacy at 12 hours (excellent/good efficacy defined as ≤35% increase in hemorrhage volume/thickness). Safety outcomes included occurrence of thrombotic events and death at 30 days. Results: A total of 227 patients with ICrH were included in the safety population (51.5% male; mean age 79.3 years) and 171 in the efficacy population (99 spontaneous and 72 traumatic bleeds). In efficacy evaluable patients, excellent/good hemostasis 12 hours postandexanet occurred in 77 out of 98 (78.6%) and in 58 out of 70 (82.9%) patients with spontaneous and traumatic bleeding, respectively. In the subanalysis by FXa inhibitor treatment group in the efficacy population, median of percent change in anti-FXa from baseline to nadir showed a decrease of 93.8% for apixaban-treated patients (n=99) and by 92.6% for rivaroxaban-treated patients (n=59). Within 30 days, death occurred in 34 out of 227 (15.0%) patients and thrombotic events occurred in 21 out of 227 (9.3%) patients (safety population). Conclusions: Andexanet reduced anti-FXa activity in FXa inhibitor-treated patients with ICrH, with a high rate of hemostatic efficacy. Andexanet may substantially benefit patients with ICrH, the most serious complication of anticoagulation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02329327.

Low-dose versus standard-dose four-factor prothrombin complex concentrate for factor-Xa inhibitor reversal in spontaneous and traumatic intracranial hemorrhage.

STUDY OBJECTIVES: Current neurocritical care guidelines recommend 50 IU/kg four-factor prothrombin complex concentrate (4PCC) for factor Xa inhibitor (FXaI) reversal in intracranial hemorrhage (ICH) based on few clinical studies conducted among non-ICH subjects. Two recent studies suggest that low-dose (25 IU/kg) 4PCC may be similar to 50 IU/kg in reversal of FXaI in ICH, and both 25 and 50 IU/kg doses are used in clinical practice for this indication. To our knowledge, no studies have directly compared 25 IU/kg versus 50 IU/kg 4PCC for FXaI reversal in ICH. The purpose of this study is to determine whether there is a difference in hemostatic efficacy between 25 IU/kg versus 50 IU/kg 4PCC for FXaI reversal in ICH. DESIGN: This multicenter, retrospective cohort study was performed in five hospitals in central Texas from November 2013 to December 2019. DATA SOURCE: Patients were identified with a medication use report of 4PCC and were classified in the low- or standard-dose group based on whether the 25 IU/kg or 50 IU/kg dose was received, respectively. PATIENTS: A total of 93 patients were included (25 IU/kg, n = 62; 50 IU/kg, n = 31). MEASUREMENTS AND MAIN RESULTS: There was no difference in hemostatic efficacy between groups (82.3% low dose vs. 83.9% standard dose, p = 0.846). No differences were identified in-hospital mortality, length of stay, thrombotic events, or the need for surgery or additional blood products between groups. CONCLUSION: For the reversal of FXaI in ICH, a 25 IU/kg dose may be an effective alternative to 50 IU/kg 4PCC dosing.