Reversal agents for novel anticoagulants

Cationic arginine-rich peptides represent a novel class of peptides being developed as neuroprotective agents for stroke and other acute and chronic neurological disorders. As a group, cationic arginine-rich peptides have a diverse range of other biological properties including the ability to traverse cell membranes, modulate immune responses, antagonise ion channel receptor function, as well as possessing cardioprotective, anti-nociceptive, anti-microbial and anti-cancer properties. A sound understanding of their safety profile is essential for the design of future clinical trials and for ensuring translational success with these compounds...

BACKGROUND: Andexanet alfa, a novel anticoagulation reversal agent for factor Xa inhibitors, was recently approved. Traumatic intracranial hemorrhage presents a prime target for this drug. The Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors study established the efficacy of andexanet alfa in reversing factor Xa inhibitors. However, the association between anticoagulation reversal and traumatic intracranial hemorrhage progression is not well understood. The objective of this study was to determine progression rates of patients with traumatic intracranial hemorrhage on factor Xa inhibitors prior to hospitalization who were managed without the use of andexanet alfa...

Introduction: Tranexamic acid (TXA) is an antifibrinolytic agent currently approved and utilized in the treatment of dysfunctional uterine bleeding, traumatic extracranial hemorrhage, anterior epistaxis, and dental procedures on patients with hemophilia. There is a paucity of literature evaluating the use of TXA for hemostasis in patients on direct oral anticoagulants (DOACs). Case Report: Our patient, a 72 year-old male on rivaroxaban, presented with persistent bleeding following a punch biopsy of the buccal mucosa...

INTRODUCTION: High incidence of bleeding events remains a key risk for patients taking anticoagulants, especially those in need of long-term combination therapy with antiplatelet agents. As a consequence, patients may not receive clinically indicated combination antithrombotic therapy. Here, we report on VE-1902, a member of a novel class of precision oral anticoagulants (PROACs) that combines effective anticoagulation with reduced bleeding in preclinical testing. METHODS AND RESULTS: Acting through covalent, reversible active-site modification of thrombin similar to a previously described molecule [1], VE-1902 shows potency and selectivity for thrombin inhibition in human plasma comparable to clinically relevant direct thrombin inhibitors (DTI) such as argatroban and dabigatran (thrombin generation assay ETP EC50  = 1...

BACKGROUND: Intracerebral hemorrhage (ICH)1 is characterized by the pathological accumulation of blood within the brain parenchyma, most commonly associated with hypertension, arteriovenous malformations, or trauma. However, it can also present in patients receiving antithrombotic drugs, either anticoagulants such as acenocoumarol/warfarin-novel oral anticoagulants or antiplatelets, for the prevention and treatment of thromboembolic disease. OBJECTIVE: The purpose of this review is to present current bibliographic data regarding ICH irrespective of the cause, as well as post-hemorrhage use of antithrombotic agents...

BACKGROUND: Individuals on anticoagulation therapy are at increased risk of bleeding, including epistaxis. There is a lack of available reversal agents for novel oral anticoagulation therapy. OBJECTIVE: This paper reviews the current literature on epistaxis in the context of novel oral anticoagulation use, in order to recommend guidelines on management. METHOD: A comprehensive search of published literature was conducted to identify all relevant articles published up to April 2019...

Determining whether a patient has taken a direct oral anticoagulant (DOAC) is critical during the periprocedural and preoperative period in the emergency department. However, the inaccessibility of complete medical records, along with the generally inconsistent sensitivity of conventional coagulation tests to these drugs, complicates clinical decision making and puts patients at risk of uncontrollable bleeding. In this study, we evaluate the utility of inhibitor-II-X (i-II-X), a novel, microfluidics-based diagnostic assay for the detection and identification of Factor Xa inhibitors (FXa-Is) in an acute care setting...

INTRODUCTION: Guidelines for imaging anticoagulated patients following a traumatic injury are unclear. Interval CT head (CTH) is often routinely performed after initial negative CTH to assess for delayed intracranial hemorrhage (ICH-d). The rate of ICH-d for patients taking novel oral anticoagulants (NOACs) is unknown. We hypothesized that the incidence of ICH-d in patients on NOACs would be similar, if not lower to that of warfarin, and routine repeat CTH after initial negative would not change management, and thus, may not be indicated...

Direct oral anticoagulants are now commonplace, and reversal agents are recently becoming available. Andexanet alfa (AnXa), approved by the United States Food and Drug Administration in 2018, is a novel decoy molecule that reverses factor Xa inhibitors in patients with major hemorrhage. We present a case of a 70-year-old man taking rivaroxaban with hemodynamic instability from a ruptured abdominal aortic aneurysm. He received AnXa prior to endovascular surgery, and intraoperatively he could not be heparinized for graft placement...

Traumatic brain injuries in patients on antithrombotic agents carry significant morbidity. Initial therapy is centered around reversal of these agents. The thromboelastogram (TEG) maps the clotting cascade to guide reversal. A retrospective chart review was conducted for 118 patients presenting with a traumatic brain injury while on antithrombotics. Patients were divided between those who received a TEG on arrival and those who did not. The primary endpoint was overall mortality. Secondary endpoints included blood product utilization, and outcomes associated with specific novel anticoagulants...

Anticoagulated older adults suffering ground-level falls are a specialty trauma population at risk for intracranial hemorrhage (ICH). Delays in diagnosis or initiation of anticoagulation reversal can lead to increased morbidity/mortality. A novel "Headstrike" protocol was implemented to improve the treatment efficacy and disposition of these patients. The study objective was to determine effectiveness of the "Headstrike" protocol in providing these patients with timely treatment and disposition, while maintaining positive outcomes...

BACKGROUND: Protein Z-dependent protease inhibitor (ZPI), is an important anticoagulant protein in plasma that functions in complex with its cofactor, protein Z (PZ) to rapidly inhibit activated factor X (FXa) on a procoagulant membrane surface. Recent studies suggest that the ZPI-PZ anticoagulant complex is a promising target for restoring hemostasis in hemophilia (Girard, et al, J Thromb Haemost, 2019, 17, 149-156). OBJECTIVE: Engineering a ZPI mutant as a novel antagonist of ZPI anticoagulant function...

Direct oral anticoagulants (DOACs) are used for many conditions where anticoagulation is needed such as non-valvular atrial fibrillation, deep vein thrombosis (DVT) and pulmonary embolism (PE). These novel agents have become popular since they do not require monitoring of therapeutic levels and there is a lower risk of certain bleeding complications when compared to warfarin. However, the efficacy and side effect profile of these agents have not been widely studied in certain patient cohorts, namely cancer patients and patients on immunomodulators or hormone analogs...

Novel oral anticoagulants (NOACs) are no longer "novel" but their reversal agents definitely are. Although NOACs enjoy high clinical efficacy, monitoring and reversal of their effect is a challenge which this review attempts to surmount. Ideally, for NOAC activity measurement, specific anti-Factor IIa levels and anti -Factor Xa levels should be monitored (chromogenic assays), but such tests are not readily available. Modifications of the existing coagulation tests catering to this unmet need for quantification of DOAC activity have been reviewed...

Objective: The purpose of this article is to review the available clinical trial data for andexanet alfa and its role in clinical practice. Data Sources: A MEDLINE/PubMed search was conducted (January 2000 to January 2019) using the keyword andexanet alfa for clinical trials. References of identified articles were searched by hand for additional citations. Study Selection and Data Extraction: We included English-language articles related to the Food and Drug Administration (FDA) approval of andexanet alfa or provided novel information regarding this drug entity...

Non-vitamin K oral anticoagulants (NOACs), including dabigatran, rivaroxaban, apixaban, and edoxaban, are increasingly used for thromboembolism prevention. Contrary to older anticoagulants, such as coumadin, when antidotes existed and were broadly used in cases of emergent surgery and bleeding, antidotes for NOACs have not been developed until recently. Moreover, the monitoring of NOAC's anticoagulant effect varies across different hospital settings and the absence of a single test that can accurately predict the degree of anticoagulation achieved increases the uncertainty...

The direct oral anticoagulants (DOACs) currently require no monitoring for routine therapy of atrial fibrillation or venous thromboembolism. Measurement of activity, however, may be important in patients with major and life-threatening bleeding, patients needing emergent surgery, in reversal situations, or in patients at high risk of bleeding or thrombosis due to underlying conditions. For these patients, a widely available and rapid turnaround assay would be optimal. To date, there is no such assay available, especially for the direct factor Xa inhibitors...

Introduction : Atrial fibrillation (AF) is associated with high morbidity and mortality rates due to thromboembolic complications, and anticoagulation is central to the management of this common arrhythmia to prevent acute thromboembolic events. The traditional anticoagulants: heparin, fondaparinux, and vitamin K antagonists (VKA, e.g. warfarin, acenocoumarol or phenprocoumin) have long served as pharmacotherapy for ischemic stroke prophylaxis. Areas covered : In this review article, the authors provide an overview on current and emerging pharmacotherapy for ischemic stroke prevention...

Direct oral anticoagulants (DOACs) are rapidly gaining popularity as alternatives to warfarin in the prevention of stroke or systemic embolic events because of the simplicity of their dosing and lack of monitoring requirement. Many physicians feared that these novel agents would be cost-prohibitive not only in their administration but also in their sequelae of bleeding, given the few reversal agents available. Whereas the medication itself is more expensive than traditional warfarin, the total cost of a hospital admission has not been compared between patients on DOACs and warfarin who have sustained a blunt traumatic intracranial hemorrhage (ICH)...

INTRODUCTION: Novel oral anticoagulant (NOAC) use is increasing in trauma patients. The reversal of these agents after hemorrhage is still evolving. The aim of our study was to evaluate outcomes after traumatic brain injury in patients on NOACs. METHODS: 3-year (2014-2016) analysis of our prospectively maintained traumatic brain injury (TBI) database. We included all TBI patients with intracranial hemorrhage (ICH) on anticoagulants. Patients were stratified into two groups, those on NOACs and on warfarin, and were matched in a 1:2 ratio using propensity score matching for demographics, injury and vital parameters, type, and size of ICH...