Thrombin Inhibitor Dabigatran Research Articles

The role of delayed head CT in evaluation of elderly blunt head trauma victims taking antithrombotic therapy

Increasing active longevity has created an increasing surge of elderly trauma patients. The majority of these patients suffer blunt trauma and many are taking antithrombotic agents. The literature is mixed regarding the utility of routine repeat head CT in patients taking antithrombotic medications with a GCS of 15 and initial negative head CT. We hypothesized that scheduled delayed CT head 12h after admission (D-CTH) in elderly blunt trauma victims would not identify clinically significant new hemorrhages or change management. A retrospective chart review using our institutional trauma registry of patients ≥65years sustaining blunt head injuries from 2010 to 2012 was performed. By hospital protocol, all such patients on antithrombotic therapy receive a routine D-CTH. All of these patients were included. Demographics, injuries, medications, laboratory values, LOS, mental status, and management were analyzed. Of the 234 patients meeting inclusion criteria, 8 initially were identified as having D-ICH. Upon further review, five patients had the same findings on both initial and delayed CT scans and one patient was determined to actually have had a hemorrhage stroke. Ultimately, only two patients (0.85%, 95% CI 0.1-3.1%) had new ICH discovered on D-CTH. None of the patients on warfarin demonstrated any new injury on D-CTH (95% CI≤4.6%). Only one patient taking aspirin as a sole agent had a delayed injury on D-CTH (1.1%, 95% CI 0-4.2%). The remaining patient was taking a combination of aspirin and clopidogrel representing 2.2% of 45 patients on combination therapy (95% CI 0.1-11.8%). Only two patients taking a direct thrombin inhibitor (dabigatran) met inclusion criteria and neither endured a bleed (95% CI≤77.6%). Further analysis revealed no cases with clinical changes or surgical intervention for new ICH on delayed imaging. No inference could be made to predict which patients would suffer D-ICH. D-CTH in elderly trauma patients taking antithrombotic agents shows no statistically significant or clinical benefit for diagnosing delayed intracranial hemorrhage after minor head injury. In those with delayed imaging showing new ICH, management was not significantly altered. Not enough data were available to predict which patients would develop D-ICH, even if asymptomatic.

The non-vitamin K antagonist oral anticoagulants (NOACs) and extremes of body weight—a systematic literature review

The non-vitamin K antagonist oral anticoagulants (NOACs) exert their anticoagulant effect closely related to their plasma concentrations. Since their distribution volume is related to body weight (and its correlates, i.e., surface area and body mass index, BMI), extremes in body weight may affect their efficacy or safety. Four NOACs are currently available for long-term use, with few exceptions, in atrial fibrillation and venous thromboembolism: the direct thrombin inhibitor dabigatran etexilate, and the factor (F) Xa inhibitors rivaroxaban, apixaban, and edoxaban. Experience in patients with low (<50kg) or extremely high (>150kg) body weight is still quite limited, as such patients were rare in registration trials and sometimes directly excluded. In general, increased bleeding and higher mortality rates are observed in patients weighing <50kg compared with patients weighing 50-100kg. This may however also be explained by the presence of underlying conditions such as cancer. At the opposite end of the spectrum of body weight, lower antithrombotic efficacy may occur, perhaps due to the dilutional effect of a higher distribution volume. In this article, we review the pertinent literature and analyze the effects of low or high body weight on anticoagulant activity and clinical outcomes of the NOACs, their dose recommendations, and areas of uncertainty.

Thrombin contributes to protective immunity in pneumonia‐derived sepsis via fibrin polymerization and platelet–neutrophil interactions

Background Innate immunity and coagulation are closely linked during sepsis. Their interaction can be detrimental to the outcome because of microvascular failure but can also enhance host defense. The role of thrombin therein has not been fully elucidated. Objective We aimed to investigate the contribution of thrombin to the host response during pneumonia-derived sepsis. Methods Mice treated with the specific thrombin inhibitor dabigatran or control chow were infected with the common human sepsis pathogen Klebsiella (K.) pneumoniae via the airways. In subsequent infection experiments, mice were additionally treated with ancrod to deplete fibrinogen. Ex vivo Klebsiella growth was assessed by incubating human whole blood or specific blood components in various conditions with Klebsiella. Results Thrombin inhibition by dabigatran enhanced bacterial outgrowth and spreading, and accelerated mortality. Thrombin inhibition did not influence neutrophil recruitment to the lung or activation or neutrophil extracellular trap formation. Dabigatran reduced D-dimer formation and fibrin deposition in the lung. Fibrin depletion also enhanced bacterial outgrowth and spreading, and thrombin inhibition had no additional effect. Both thrombin and fibrin polymerization inhibited ex vivo Klebsiella outgrowth in human whole blood, which was neutrophil dependent, and the effect of thrombin required the presence of platelets and platelet protease activated receptor-1. In vivo thrombin inhibition reduced platelet-neutrophil complex formation and endothelial cell activation, but did not prevent sepsis-induced thrombocytopenia or organ damage. Conclusions These results suggest that thrombin plays an important role in protective immunity during pneumonia-derived sepsis by fibrin polymerization and enhancement of platelet-neutrophil interactions.

Determination of non-Vitamin K oral anticoagulant (NOAC) effects using a new-generation thrombelastography TEG 6s system.

Non vitamin K oral anticoagulants (NOACs) do not require regular monitoring but information about their pharmacodynamic effect may be importantin situations like trauma, stroke oremergent surgery. Currently, no standardized point-of-care test is available to evaluate the anticoagulant effects of NOACs. We evaluated the anticoagulant effect of NOACs with the next generation point-of-care TEG assay (TEG® 6S) based on a fully-automated thrombelastography system. We used two TEG® 6S assays, the DTI assay and Anti-Factor Xa (AFXa) assay, to detect anticoagulant effects and classify NOACs. Blood from healthy volunteers (n = 26) was used to obtain a baseline reference range. Data derived from patients on factor Xa inhibitors (FXi) (rivaroxaban and apixaban) (n = 39), and direct thrombin inhibitors (DTIs) (dabigatran) (n = 25) were compared against the reference range for detection of drug effect and drug classification. TEG®6s R-time highly correlated to each NOAC. Presence of NOACs caused elongation of R-time on the AFXa assay compared to the reference range (4.3 ± 1.7 vs. 1.3 ± 0.3min. for FXi, p < 0.001 and 3.5 ± 1.2 vs. 1.3 ± 0.3min. for DTI, p < 0.001). R-time on the DTI assay was elongated only in presence of a DTI (3.4 ± 1.0 vs. 1.5 ± 0.2min, p < 0.001). The cutoff for detection of a DTI effect was an R time of 1.9min and for anti-Xa effect was 1.95min. For detection of NOAC therapy, there was ≥92% sensitivity and ≥95% specificity. The automated TEG®6s NOAC assay may be an effective tool to identify an anticoagulant effect from NOAC therapy and facilitate care of patients with bleeding or at risk of bleeding in the event of needing emergency surgery.

Italian intersociety consensus on DOAC use in internal medicine.

The direct oral anticoagulants (DOACs) are drugs used in clinical practice since 2009 for the prevention of stroke or systemic embolism in non-valvular atrial fibrillation, and for the treatment and secondary prevention of venous thromboembolism. The four DOACs, including the three factor Xa inhibitors (rivaroxaban, apixaban and edoxaban) and one direct thrombin inhibitor (dabigatran) provide oral anticoagulation therapy alternatives to Vitamin K antagonists (VKAs). Despite their clear advantages, the DOACs require on the part of the internist a thorough knowledge of their pharmacokinetic and pharmacodynamic characteristics to ensure their correct use, laboratory monitoring and the appropriate management of adverse events. This document represents a consensus paper on the use of DOACs by representatives of three Italian scientific societies: the Italian Society of Internal Medicine (SIMI), the Federation of the Associations of Hospital Managers (FADOI), and the Society for the Study of Haemostasis and Thrombosis (SISET). This document formulates expert opinion guidance for pragmatic managing, monitoring and reversing the anticoagulant effect of DOACs in both chronic and emergency settings. This practical guidance may help the internist to create adequate protocols for patients hospitalized ion internal medicine wards, where patients are often elderly subjects affected by poly-morbidities and renal insufficiency, and, thus, require particular attention to drug-drug interactions and peri-procedural protocols.

MODERN APPROACHES TO ANTICOAGULANT THERAPY OF PULMONARY EMBOLISM: FOCUS ON RIVAROXABAN

The analytical article provides a modern state of the anticoagulant therapy in pulmonary thromboembolism. Major advantages and preferential use of direct selective peroral anticoagulants represented by thrombin inhibitor dabigatran and a Xa factor inhibitors composed of apixaban, edoxaban and rivaroxaban. Attention is focused on rivaroxaban the evidence base of which in pulmonary thromboembolism was widened in 2017 by data of the EINSTEIN CHOICE study. Its results allow considering the use of the rivaroxaban 10 mg 1 time per day as a possibility of long-term, actually many year prevention of the pulmonary thromboembolism after the end of the standard course of the therapeutic anticoagulation involving use of a high dosage of the drug (15 mg 2 times per day) for 3 weeks actually from the moment of the disease diagnostics and continuation for 6-12 months of the drug administration at a dose of 20 mg 1 time per day. As a result for many patients with pulmonary thromboembolism use of rivaroxaban at various dosages without transfer to another coagulant allows considerably satisfying the requirements in antithrombotic therapy at various stages of such patients management.

SAFETY OF DIRECT ORAL ANTICOAGULANTS IN PATIENTS WITH ATRIAL FIBRILLATION: A TWO-YEAR COHORT STUDY

Real-life clinical application of anticoagulant drugs is currently one of the most promising trends in cardiology. With relation to initial prescription of anticoagulants, the updated 2016 guidelines on the management of patients with atrial fibrillation (AF) highlight direct oral anticoagulants (DOAC) rather than vitamin K antagonists, but, unfortunately, they are not clear about whether different DOAC have the same clinical effect of there is a significant difference. Material and methods . We conducted a comparative analysis of the safety of DOAC in patients with non-valvular AF and attempted to identify the potential predictors of hemorrhagic events in order to assess the predictive value of bleeding risk scores. For this purpose, we observed 117 patients with non-valvular AF who received DOAC to prevent TEC for 2 years (24 months). Results. Over the entire period of follow-up, no major bleeding or thromboembolic complications were recorded, supporting the good efficacy and safety profile of DOAC. We analysed the prognostic value of various scores and found that HAS-BLED had the highest predictive value in the group of patients treated with the direct thrombin inhibitor (dabigatran). Treatment with factor Xa inhibitors (rivaroxaban and apixaban) did not demonstrate a similar trend. Conclusion. Over the 2-year follow-up of 117 patients treated with DOAC, we were able to show that this group of drugs in patients with non-valvular AF is effective and safe given that adequate doses in accordance with the instructions are administered; this is true for both direct thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban and apixaban). HAS-BLED was prognostically more accurate when the direct thrombin inhibitor dabigatran was administered.

The Severity of Intracranial Hemorrhages Measured by Free Hemoglobin in the Brain Depends on the Anticoagulant Class: Experimental Data.

Background and Purpose. Anticoagulant therapy is broadly used to prevent thromboembolic events. Intracranial hemorrhages are serious complications of anticoagulation, especially with warfarin. Direct oral anticoagulants reduce but do not eliminate the risk of intracranial hemorrhages. The aim of this study is to determine the degree of intracranial hemorrhage after application of anticoagulants without additional triggers. Methods. Rats were treated with different anticoagulant classes (vitamin K antagonists, heparin, direct thrombin inhibitor, and factor Xa inhibitor). Brain hemorrhages were assessed by the free hemoglobin concentration in the brain parenchyma. Results. Vitamin K antagonists (warfarin and brodifacoum) significantly increased free hemoglobin in the brain. Among direct oral anticoagulants, thrombin inhibitor dabigatran also significantly increased free hemoglobin in the brain, whereas treatment with factor Xa inhibitor rivaroxaban did not have significant effect on the free hemoglobin concentration. Conclusions. Our data indicates that the severity of brain hemorrhages depends on the anticoagulant class and it is more pronounced with vitamin K antagonists.

A MODERN APPROACH TO THE TREATMENT AND PROPHYLAXIS OF VENOUS THROMBOEMBOLISM. THE ROLE OF NEW ORAL ANTICOAGULANTS. Part I

The article highlights the burden of the venous thromboembolism (VTE) in clinical practice as one of the most frequent cause of cardiovascular death and disabling embolic stroke worldwide. The author compares the traditional use of VKA antagonists and new class of oral anticoagulants— direct thrombin and factor Xa inhibitors (dabigatran, rivaroxaban, apixaban) for VTE treatment and prevention. The results of most significant randomized clinical trials in VTE area and the latest international guidelines are also discussed.

EXPERIENCE IN THE USE OF ORAL ANTICOAGULANTS IN OUTPATIENT CLINICS

Since 2011, with the emergence of new classes of antithrombotic drugs – inhibitors of the activated X coagulation factor (rivoroxaban, apixaban, edoxaban) and thrombin inhibitor (dabigatran), antithrombotic therapy has received a new impetus to development and wider introduction into practice. New oral anticoagulants (NOAC) do not require laboratory monitoring for correction and dose selection, which makes their appointment more simple and convenient, compared with vitamin K antagonists (warfarin). The purpose of the presented work was to evaluate the efficacy and The safety of anticoagulant therapy in patients with atrial fibrillation in out-patient practice. The study was conducted for 1 year. There were 168 patients (108 men, 60 women, mean age 70. 6 ± 2.46 years) with atrial fibrillation. 90 patients received PLA (53% – dabigatran, 41% – rivaroxaban, 6% – apixaban), 78 – warfarin. 74% of patients included in the study had 3 or more points on the scale CHA2DS2-Vasc. During the observation period in the PLA group, ONMC was registered in 2 patients (2.2%), PE – 0. In 1 patient, embolism in the brachial artery was observed against the background of anticoagulant withdrawal due to the planned surgical intervention. In the group receiving warfarin as an anticoagulant, 2 strokes were registered during the year (2.3%) (1 of them fatal). The frequency of bleeding in the PLA group: large – 0, macrogematuria – 3, nasal 2, conjunctival – 2. In the warfarin group: large – 1 (fatal stratification of the aneurysm of the abdominal aorta), macrogemaria – 4, nasal 1, conjunctival – 1. Reliable differences in The frequency of bleeding was not revealed.

Gastrointestinal bleeding in patients on novel oral anticoagulants: Risk, prevention and management.

Novel oral anticoagulants (NOACs), which include direct thrombin inhibitor (dabigatran) and direct factor Xa inhibitors (rivaroxaban, apixaban and edoxaban), are gaining popularity in the prevention of embolic stroke in non-valvular atrial fibrillation as well as in the prevention and treatment of venous thromboembolism. However, similar to traditional anticoagulants, NOACs have the side effects of bleeding, including gastrointestinal bleeding (GIB). Results from both randomized clinical trials and observations studies suggest that high-dose dabigatran (150 mg b.i.d), rivaroxaban and high-dose edoxaban (60 mg daily) are associated with a higher risk of GIB compared with warfarin. Other risk factors of NOAC-related GIB include concomitant use of ulcerogenic agents, older age, renal impairment, Helicobacter pylori infection and a past history of GIB. Prevention of NOAC-related GIB includes proper patient selection, using a lower dose of certain NOACs and in patients with renal impairment, correction of modifiable risk factors, and prescription of gastroprotective agents. Overt GIB can be managed by withholding NOACs followed by delayed endoscopic treatment. In severe bleeding, additional measures include administration of activated charcoal, use of specific reversal agents such as idarucizumab for dabigatran and andexanent alfa for factor Xa inhibitors, and urgent endoscopic management.

Overview of the Direct Oral Anticoagulants

ABSTRACT Over the past 6 decades, warfarin has proven efficacious in reducing stroke risk in patients with atrial fibrillation and reducing the risk of recurrent venous thromboembolism in patients with acute deep vein thrombosis or pulmonary embolism. However, there have been multiple challenges with using warfarin including delayed onset of action, need for bridging and monitoring as well as many drug-drug and drug-food interactions. Hence, long years of research have led to the development of direct oral anticoagulants. Of the 4 direct oral anticoagulants currently approved by the Food and Drug Administration, 1 is a direct thrombin inhibitor (dabigatran) and the other 3 are direct factor Xa inhibitors (apixaban, rivaroxaban and edoxaban). Direct oral anticoagulants have been found to be at least as effective as warfarin with fewer bleeding complications. This paper provides an overview of the evolution of anticoagulation therapies and an extensive literature review of the new direct oral anticoagulants.

GASTROINTESTINAL BLEEDING WITH THE USE OF NEW ORAL ANTICOAGULANTS: EPIDEMIOLOGY, RISK FACTORS, TREATMENT, AND PREVENTION

Novel oral anticoagulants (NOACs), such as the direct thrombin inhibitor dabigatran and the selective factor Xa inhibitors rivaroxaban and apixaban, are increasingly used as an effective antithrombotic drug in real clinical practice. Unfortunately, these medications can cause severe adverse events, including gastrointestinal bleeding, one of the most common events. This complication annually develops in 2–3% of patients taking NOACs. The sources of bleeding can be in both the upper or lower gastrointestinal tract (GIT). The common cause of bleeding is undiagnosed GIT neoplasms, often colorectal cancer. Clinical and cohort studies show that the greatest risk of bleeding is observed with the use of rivaroxaban. The risk factors are advanced age, concurrent administration of nonsteroidal anti-inflammatory drugs, aspirin, and other anticoagulants, gastrointestinal diseases, H. pylori infection, impaired renal and hepatic functions, and alcohol intake. Gastrointestinal bleeding is treated on general principles, by applying endoscopic and surgical techniques. Particular importance is attached to the blockade of the anticoagulant effects of NOACs. For this, the entire range of antidotes, such as idarucizumab (it has been already applied in several countries of the world), andexanet, and ciraparantag, has been recently designed and is undergoing clinical trials. Bleeding prevention involves control of risk factors, rational use of NOACs, prophylactic administration of proton pump inhibitors, timely discontinuation of anticoagulation prior to traumatic medical procedures on the gastrointestinal organs (before certain endoscopic procedures in particular).

Dabigatran Potentiates Gemcitabine-Induced Growth Inhibition of Pancreatic Cancer in Mice

Pancreatic cancer is one of the most lethal solid malignancies, with few treatment options. We have recently shown that expression of protease activated receptor (PAR)-1 in the tumor microenvironment drives the progression and induces the chemoresistance of pancreatic cancer. As thrombin is the prototypical PAR-1 agonist, here we address the effects of the direct thrombin inhibitor dabigatran on pancreatic cancer growth and drug resistance in an orthotropic pancreatic cancer model. We show that dabigatran treatment did not affect primary tumor growth, whereas it significantly increased tumor dissemination throughout the peritoneal cavity. Increased dissemination was accompanied by intratumoral bleeding and increased numbers of aberrant and/or collapsed blood vessels in the primary tumors. In combination with gemcitabine, dabigatran treatment limited primary tumor growth, did not induce bleeding complications and prevented tumor cell dissemination. Dabigatran was, however, not as efficient as genetic ablation of PAR-1 in our previous study, suggesting that thrombin is not the main PAR-1 agonist in the setting of pancreatic cancer. Overall, we show that dabigatran potentiates gemcitabine-induced growth inhibition of pancreatic cancer but does not affect primary tumor growth when used as monotherapy.

Dabigatran Therapy Resulting in the Resolution of Rivaroxaban-resistant Left Atrial Appendage Thrombi in Patients with Atrial Fibrillation.

Patients with persistent atrial fibrillation (AF) and a large left atrium are at a high risk for thromboembolisms. Recently, direct oral anticoagulants (DOACs) have mainly been used for the prevention of cardiac embolisms caused by AF. Transesophageal echocardiography (TEE) is performed in order to exclude any left atrial appendage (LAA) thrombi. We herein report two cases of persistent AF, both of which were treated with rivaroxaban for more than two years. Since TEE identified mobile LAA thrombi with this treatment, we switched from rivaroxaban to the direct thrombin inhibitor dabigatran. Dabigatran resolved the LAA thrombi that had been refractory to rivaroxaban.

Rationale and Design of a Phase III Safety Trial of Idarucizumab in Children Receiving Dabigatran Etexilate for the Treatment and Secondary Prevention of Venous Thromboembolism

Introduction: The frequency of venous thromboembolism (VTE) is increasing in children. Dabigatran etexilate (DE), the prodrug of the direct thrombin inhibitor dabigatran is approved for use in adults for the treatment and secondary prevention of VTE. However, DE is not approved for the use in children and is currently being evaluated for the treatment and secondary VTE prevention within ongoing pediatric DE trials. With the increasing use of oral anticoagulants for VTE treatment and prevention in adults, agents that can rapidly reverse anticoagulant effects in patients who require emergency surgery/urgent procedure, or who have a rare event of life-threatening or uncontrolled bleeding, will complement treatment strategies for managing bleeds or urgent interventions in patients receiving dabigatran. Idarucizumab is a humanized monoclonal antibody fragment that provides immediate, complete and sustained reversal of the anticoagulation effects of dabigatran. The safety and efficacy of idarucizumab have been confirmed in adult patients receiving DE; however, the safety of idarucizumab in children with VTE remains to be established. The present trial will investigate the safety of idarucizumab in children with VTE who have participated in two ongoing clinical trials investigating DE.Methods: A phase III, open-label, single arm, global multicenter safety trial (approximately 25-40 sites; approximately 10 countries) is planned in children (aged < 18 years; n = ~5) recruited within the ongoing dabigatran pediatric clinical program for treatment or secondary prevention of VTE. Children who require a rapid reversal of anticoagulation will be eligible for trial inclusion: those with life-threatening/uncontrolled bleeding (group A) and those without bleeding but needing emergency surgery/urgent procedures (group B). Patients will receive a single intravenous dose of idarucizumab (up to 5 g, calculated according to the patient’s body weight, administered in two equally divided infusions or injections given not more than 15 minutes apart) and will be monitored for 30 days.Results: The primary endpoint will be the safety of idarucizumab assessed by the occurrence of drug-related adverse events (including immune reactions) and all-cause mortality. The secondary endpoints will be the percentage change of coagulation tests (diluted thrombin time [dTT] and ecarin clotting time [ECT]) at 30 minutes post-dose versus pre-dose, the time to achieve complete reversal, duration of complete reversal of dabigatran's anticoagulant effect sustained at 24 hours post-dose based on coagulation tests (dTT and ECT), and the formation of antidrug antibodies at 30 days post-dose. Cessation of bleeding, bleeding status and other clinical conditions that may contribute to bleeding (group A patients only) will also be assessed. Data will be reported using descriptive statistics and all treated patients will be included in the safety analysis.Conclusion: This trial will report the safety of idarucizumab in children with VTE who require the rapid, complete and sustained reversal of the anticoagulant effects of dabigatran. DisclosuresAlbisetti:Boehringer Ingelheim: Other: Pediatric Expert Working Group. Schlosser:Boehringer Ingelheim: Employment. Brueckmann:Boehringer Ingelheim: Employment. Gropper:Boehringer Ingelheim: Employment. Glund:Boehringer Ingelheim: Employment. Tartakovsky:Boehringer Ingelheim: Employment. Reilly:Boehringer Ingelheim: Employment.

Dabigatran Is Associated with a Significantly Lower Risk of Abnormal Uterine Bleeding Than Warfarin in Female Patients of Childbearing Age with Venous Thromboembolism

▪Introduction: While Direct Oral Anticoagulants (DOACs) have been shown to have an overall equal efficacy as and better safety profile than warfarin in patients with acute venous thromboembolism (VTE), Xa-inhibitors have been associated with a higher risk of abnormal uterine bleeding (AUB). No data regarding AUB with the direct thrombin inhibitor dabigatran etexilate (dabigatran) have been reported to date.Aim: To determine the risk of AUB during anticoagulation with dabigatran compared to warfarin in female VTE patients aged 18-50 years.Methods: We performed a post hoc analysis of the pooled RE-COVER studies, two double-blind randomized trials evaluating dabigatran administered at a dose of 150mg twice daily versus warfarin after an initial treatment with parenteral anticoagulants, and the RE-MEDY trial, a double-blind randomized trial that studied the extended use of dabigatran at the same dose versus warfarin, all in patients with VTE. We compared the incidence of AUB, based on a defined preferred terms search in adverse events, in female patients aged 18-50 years who were treated with dabigatran versus who were treated with warfarin. Patients who rolled-over from RE-COVER into RE-MEDY and stayed on the same treatment were accounted for as "only one patient" taking the whole treatment period into consideration, whereas patients who switched treatment were analyzed as two different study subjects.Results: Of the 2964 women included in the above mentioned trials, 1280 women were in the relevant age category and included in the current analysis. A total of 643 patients were randomized to treatment with dabigatran and 637 to treatment with warfarin. The overall rate of AUB was 5.9% for the women treated with dabigatran and 9.6% in those treated with warfarin, for an Odds Ratio of 0.59 (95% confidence interval 0.39-0.90).Conclusion: In female VTE patients of 18-50 years old, dabigatran was associated with a significantly 41% lower risk of AUB than warfarin. DisclosuresFerreira:BMS-Pfizer: Consultancy, Other: Grant support; Bayer: Other: Grant support. Klok:Boehringer Ingelheim Pharma GmbH & Co.KG: Research Funding; Bristol-Myers Squibb: Research Funding; Bayer HealthCare: Research Funding; Daiichi-Sankyo: Research Funding. Feuring:Boehringer Ingelheim Pharma GmbH & Co.KG: Employment. Fraessdorf:Boehringer Ingelheim Pharma GmbH & Co.KG: Employment. Kreuzer:Boehringer Ingelheim: Employment. Huisman:GlaxoSmithKline: Other: Grant support; Boehringer Ingelheim Pharma GmbH & Co.KG: Other: Grant support; Bayer HealthCare: Other: Grant support; Pfizer: Other: Grant support; Actelion: Other: Grant support.

Using direct anticoagulants (DOACs) in cancer and other high risk populations

The major practical advantage of the direct oral anticoagulants (DOACs), comprising the thrombin inhibitor dabigatran and the factor Xa inhibitors apixaban, edoxaban, and rivaroxaban, over vitamin K antagonists is their fixed dosing without the need for laboratory monitoring. With the recent, rapid introduction of the DOACs for the treatment of acute venous thromboembolism (VTE), clinicians are now faced with various questions regarding the efficacy and safety of these compounds overall and in specific high-risk populations. The collective evidence from 6 large clinical trials involving 27,000 patients has demonstrated that DOACs are as effective as vitamin K antagonists (VKA) in preventing recurrent VTE while being associated with a significantly lower risk of major bleeding. These findings are consistent in subgroups of patients with pulmonary embolism, the elderly, and those patients with a high body weight or moderate renal insufficiency, making these agents suitable for a broad spectrum of patients with VTE. DOACs are also an attractive treatment option in patients with VTE and concomitant cancer, thrombotic antiphospholipid syndrome, or heparin-induced thrombocytopenia, but the currently available clinical data is insufficient to make evidence-based recommendations on the use of DOACs in these settings. Several studies evaluating the efficacy and the safety of DOACs in these high-risk populations are underway.

Anticoagulation increases alveolar hemorrhage in mice infected with influenza A.

Influenza A virus infection is a common respiratory tract infection. Alveolar hemorrhage has been reported in patients with influenza pneumonia and in mice infected with influenza A. In this study, we investigated the effect of two anticoagulants on alveolar hemorrhage after influenza A virus (IAV) infection of wild‐type mice. Wild‐type mice were anticoagulated with either warfarin or the direct thrombin inhibitor dabigatran etexilate and then infected with a mouse‐adapted influenza virus (A/Puerto Rico/8/34 H1N1). Alveolar hemorrhage was assessed by measuring hemoglobin levels in the bronchoalveolar lavage fluid (BALF). We also measured vascular permeability and viral genomes in the lung, as well as white blood cells, inflammatory mediators, and protein in BALF. Survival and body weight were monitored for 14 days after influenza A infection. In infected mice receiving either warfarin or dabigatran etexilate we observed decreased activation of coagulation in the BALF and increased alveolar hemorrhage. Warfarin but not dabigatran etexilate increased vascular permeability and mortality of influenza A‐infected mice. Anticoagulation did not affect levels of influenza A genomes, white blood cells, inflammatory mediators, or protein in the BALF. Our study indicates that systemic anticoagulation increases alveolar hemorrhage in influenza A‐infected mice.

Role of agents for reversing the effects of target-specific oral anticoagulants.

The available clinical data on target-specific oral anticoagulant (TSOAC) reversal agents that are currently in development or have been approved by the Food and Drug Administration (FDA) are reviewed. The development of TSOACs such as dabigatran, rivaroxaban, edoxaban, and apixaban has presented benefits and new challenges. One of the main challenges associated with the use of TSOACs is the lack of suitable agent-specific reversal agents. Several treatment options for the management of life-threatening bleeding events associated with TSOAC use, such as fresh frozen plasma, prothrombin complex concentrates, and recombinant coagulation factor VIIa, have been used, with inconsistent results. Currently, two potential reversal agents for oral direct factor Xa inhibitors (andexanet alfa and ciraparantag) are at various stages of clinical development. Idarucizumab, a reversal agent for the oral direct thrombin inhibitor dabigatran, was approved by FDA in October 2015. Idarucizumab and andexanet alfa have been reported to produce anticoagulation reversal effects within minutes of administration. Ciraparantag was demonstrated to decrease whole blood clotting time to within 10% of baseline values in 10 minutes or less, with a return to baseline hemostasis in 10-30 minutes. TSOAC reversal agents have been generally well tolerated in clinical trials. Idarucizumab and other TSOAC reversal agents, such as andexanet alfa and ciraparantag, present the potential for consistent and effective treatment and management options when life-threatening or uncontrolled TSOAC-associated bleeding occurs or when emergency surgery is warranted in patients using TSOACs.