Comparison of Protective Effects of Recombinant Antithrombin Gamma and Plasma-Derived Antithrombin on Sepsis-Induced Disseminated Intravascular Coagulation and Multiple Organ Failure.

In Japan, the dose of the new recombinant antithrombin III concentrate (rAT-gamma) is titrated according to patient body weight (BW), while conventional plasma-derived antithrombin concentrates (AT) are administered as a fixed dose. Therefore, it is anticipated that rAT-gamma could produce better treatment effects than AT. The aim of this study was to compare the organ protective effects of doses of rAT-gamma and AT administered in clinical practice for septic disseminated intravascular coagulation (DIC) and multiple organ failure. This study was performed at a single university hospital in Japan. A total of 49 patients with antithrombin deficiency secondary to septic DIC who were administered either rAT-gamma (n = 26) or AT (n = 23) were retrospectively analyzed to assess the dose of supplemental antithrombin concentrates, plasma antithrombin activity, Japanese Association for Acute Medicine (JAAM)-DIC score, and modified Sequential Organ Failure Assessment (SOFA) score on days 0, 3 and 6. The AT-equivalent dose per kg BW of rAT-gamma (equal to the initial rAT-gamma dose per kg BW divided by 1.2) was significantly higher than the dose per kg BW of AT (AT 23.4 ± 5.1 vs. rAT 28.9 ± 3.9 IU/kg/day; P < 0.001). Consequently, serial increases in plasma antithrombin levels occurred more rapidly in the rAT-gamma group (P = 0.036). JAAM DIC and modified SOFA scores revealed significantly greater improvement in the rAT versus the AT group (JAAM DIC score: P = 0.042, mSOFA score: P = 0.005). The results of this study suggest that AT supplementation adjusted for patient BW might further improve septic DIC and multiple organ failure.

Prospective, randomized, double-blind, placebo-controlled evaluation of the Pharmacokinetics, Safety and Efficacy of Recombinant Antithrombin Versus Placebo in Preterm Preeclampsia.

BACKGROUND: Despite expectant management, preeclampsia remote from term usually results in preterm delivery. Antithrombin, which displays antiinflammatory and anticoagulant properties, may have a therapeutic role in treating preterm preeclampsia, a disorder characterized by endothelial dysfunction, inflammation, and activation of the coagulation system. OBJECTIVE: This randomized, placebo-controlled clinical trial aimed to evaluate whether intravenous recombinant human antithrombin could prolong gestation and therefore improve maternal and fetal outcomes. STUDY DESIGN: We performed a double-blind, placebo-controlled trial at 23 hospitals. Women were eligible if they had a singleton pregnancy, early-onset or superimposed preeclampsia at 23 0/7 to 30 0/7 weeks' gestation, and planned expectant management. In addition to standard therapy, patients were randomized to receive either recombinant human antithrombin 250 mg loading dose followed by a continuous infusion of 2000 mg per 24 hours or an identical saline infusion until delivery. The primary outcome was days gained from randomization until delivery. The secondary outcome was composite neonatal morbidity score. A total of 120 women were randomized. RESULTS: There was no difference in median gestational age at enrollment (27.3 weeks' gestation for the recombinant human antithrombin group [range, 23.1-30.0] and 27.6 weeks' gestation for the placebo group [range, 23.0-30.0]; P=.67). There were no differences in median increase in days gained (5.0 in the recombinant human antithrombin group [range, 0-75] and 6.0 for the placebo group [range, 0-85]; P=.95). There were no differences between groups in composite neonatal morbidity scores or in maternal complications. No safety issues related to recombinant human antithrombin were noted in this study, despite the achievement of supraphysiological antithrombin concentrations. CONCLUSION: The administration of recombinant human antithrombin in preterm preeclampsia neither prolonged pregnancy nor improved neonatal or maternal outcomes.

Protection of the endothelial glycocalyx by antithrombin in an endotoxin-induced rat model of sepsis.

INTRODUCTION: Injury and loss of the endothelial glycocalyx occur during the early phase of sepsis. We previously showed that antithrombin has a protective effect on this structure in vitro. Here, we investigated the possible protective effects of antithrombin in an animal model of sepsis. METHODS: Wistar rats were injected with endotoxin, and circulating levels of syndecan-1, hyaluronan, albumin, lactate and other biomarkers were measured in an antithrombin-treated group and an untreated control group (n = 6 in each group). Intravital microscopy was used to observe leukocyte adhesion, microcirculation, and syndecan-1 staining. RESULTS: The circulating levels of syndecan-1 and hyaluronan were significantly reduced in the antithrombin-treated group, compared with the untreated controls. Lactate levels and albumin reduction were significantly attenuated in the antithrombin-treated group. Intravital microscopic observation revealed that both leukocyte adhesion and blood flow were better maintained in the treatment group. The syndecan-1 lining was disrupted after endotoxin treatment, and this derangement was attenuated by treatment with antithrombin. CONCLUSION: Antithrombin effectively maintained microcirculation and vascular integrity by protecting the glycocalyx in a rat sepsis model.

Cloning, Characterization and Anti-Inflammatory Properties of Bothrops jararaca Snake Antithrombin.

Antithrombin inhibits blood coagulation through the interaction with serine proteases in both intrinsic and extrinsic pathways. In addition, antithrombin also shows anti-inflammatory properties, which are independent of its effects on coagulation. This work shows for the first time the cloning and sequencing of antithrombin from a snake species. This predicted protein is composed by 430 amino acids and presents about 64.5% sequence identity to human antithrombin. Biacore experiments revealed that the binding affinity of Bothrops jararaca snake antithrombin to heparin was ~30 times higher than that of human antithrombin. Furthermore, Bothrops jararaca antithrombin is more effective in preventing acute inflammation induced by carrageenan when compared to human antithrombin. Hence, the results showed herein suggest that Bothrops jararaca antithrombin can play a key role in the control of acute inflammation and that this molecule might be used as a pharmacological tool and as a prototype for drug development.

New oral anticoagulants and their implications for dental patients.

Anticoagulation therapy is used in several conditions to prevent or treat thromboembolism. Over the last 40 years, warfarin has been the oral anticoagulant of choice and has been considered the mainstay of treatment. However, its use is limited by a narrow therapeutic index and complex pharmacodynamics, necessitating regular monitoring and dose adjustments. Recently, two new oral anticoagulants--dabigatran etexilate (a direct thrombin inhibitor) and rivaroxiban (a factor Xa inhibitor)--have been approved for use in North America and Europe. Unlike warfarin, dabigatran and rivaroxiban are relatively small molecules that work as anticoagulants by targeting specific single steps of the coagulation cascade. Their advantages, relative to warfarin, include: predictable pharmacokinetics; limited food and drug interactions; rapid onset of action; and, short half-life. They require no monitoring. However, they lack a specific reversal agent. The number of patients taking dabigatran and rivaroxaban is increasing. Therefore, it is inevitable that dentists will be required to perform invasive procedures on this cohort of patients. This paper outlines the various properties of the new oral anticoagulants and the most recent guidelines regarding the management of these dental patients taking these medications.

The changing face of oral anticoagulants.

Warfarin has been the established oral anticoagulant for the last 50 years, being effective in the prevention and treatment of venous and arterial thromboembolic disorders. However, the frequent requirement for INR monitoring, multiple drug and food interactions have fuelled the need for development of new oral anticoagulants. Dabigatran is the first of a series of new oral anticoagulants that are emerging as the successors to warfarin. This new group of anticoagulants is rapidly gaining FDA and NICE approval and has proven non-inferiority to warfarin and viable alternatives to warfarin in the coming years. Given the obvious impact of this on dental treatment in the primary care and hospital setting this article aims to increase familiarisation with this new medicine group.

[Dabigatran etexilate use among older adults in a home-care system after hip or knee replacement surgery]. / Utilización de dabigatrán etexilato en postoperatorios traumatológicos de adultos mayores en un sistema de hospitalización a domicilio.

INTRODUCTION: Hip replacement surgery (HRS) and knee replacement surgery (KRS) require long-term deep venous thrombosis (DVT) prophylaxis. This study describes dabigatran etexilate (DE) use in post-surgical older adults who underwent HRS and KRS in a clinical practice setting in a home-care system. MATERIAL AND METHODS: A retrospective descriptive cohort study included elective HRS and KRS postsurgical older adults under home care receiving either DE (n=76) or enoxaparin (n=80). DE was indicated by using the same selection criteria and dosing as in the RE-MODEL and RE-NOVATE studies. The enoxaparin 40 mg/day patients were included as historic controls when they met the same selection criteria as DE patients. Symptomatic DVT, bleeding rate, re-admission rate and mortality during the 90-day postsurgical period were analyzed. RESULTS: The mean age of the DE group was 74 (5) years old, with 74% females. There were no significant differences in age, gender and type of replacement between the two groups. There were four DVT in each group (50% proximal), with no significant differences found between groups. There was one pulmonary thromboembolism in the DE group, and one major bleeding in the enoxaparin group. There were no deaths during the 90-day follow-up; however, two re-hospitalizations occurred in the DE group. The details on introducing DE use in our home-care system are also described. CONCLUSIONS: In appropriately selected older adults DE seems to be an effective choice for DVT prophylaxis in home-care in a clinical practice setting.

A comparison of dabigatran etexilate with warfarin in patients with mechanical heart valves: THE Randomized, phase II study to evaluate the safety and pharmacokinetics of oral dabigatran etexilate in patients after heart valve replacement (RE-ALIGN).

BACKGROUND: Vitamin K antagonists are the only oral anticoagulants approved for long-term treatment of patients with a cardiac valve replacement. OBJECTIVE: This study aims to test a new dosing regimen for dabigatran etexilate in patients with a mechanical bileaflet valve. METHODS: Patients aged ≥ 18 years and ≤ 75 years, either undergoing implantation of a mechanical bileaflet valve (aortic or mitral or both) during the current hospital stay or having undergone implantation a mitral bileaflet valve >3 months before randomization, will be randomized between dabigatran etexilate or warfarin (in a ratio of 2:1) in an open-label design. Initial doses of dabigatran will be based on the estimated creatinine clearance, and the doses will be adjusted based on measuring trough dabigatran plasma levels to achieve levels ≥ 50 ng/mL at steady state. Doses will range between 150 mg twice a day and 300 mg twice a day. Warfarin management and target international normalized ratio will be according to current practice guidelines at the discretion of the treating physicians. The plan is to treat 270 patients with dabigatran etexilate for a total study population of approximately 405 patients. Clinical efficacy and safety outcomes will be analyzed in an exploratory manner. CONCLUSIONS: RE-ALIGN is the first study to test an alternative to warfarin in patients with mechanical heart valves. A definitive phase III study will be planned based on the results of this study.

Current and future alternatives to warfarin for the prevention of stroke in atrial fibrillation.

Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice and is associated with a nearly 5-fold increase in the risk of stroke. Warfarin has been the cornerstone of treatment to reduce stroke risk in AF patients for decades. Although effective in preventing thrombosis, warfarin is difficult to manage and is associated with a 1% to 7% yearly risk of major hemorrhage. Until recently, there were no effective oral alternatives to warfarin. Dabigatran etexilate, a direct thrombin inhibitor, was approved in 2010 for the reduction of stroke and systemic embolism in patients with nonvalvular AF, and the factor Xa inhibitor rivaroxaban was approved for a similar indication in 2011. Other late-stage orally administered agents that may be approved for this indication include apixaban and edoxaban; others at earlier stages of development will be discussed in this review as well. Nonpharmacological approaches to stroke prevention include left atrial appendage removal, ligation, or occlusion. This review examines advances in the management of stroke risk in AF patients, focusing on recently marketed and late-stage modalities. The advent of alternatives to warfarin for reducing stroke risk in AF patients may improve physicians' ability to offer safe and effective stroke prevention in all AF patients.

Plasma-diluted thrombin time to measure dabigatran concentrations during dabigatran etexilate therapy.

New anticoagulants, like the orally available direct thrombin inhibitor (DTI) dabigatran etexilate, have recently been introduced into the market for venous thromboembolic prophylaxis and for stroke prevention in atrial fibrillation. While dabigatran has been approved for use without the need for routine therapeutic monitoring, there are clinical scenarios in which monitoring can help guide clinical management. We report herein the application of a recently described plasma-diluted thrombin time (DTI assay) used to monitor intravenous DTI as a useful and easily implemented method to monitor oral DTIs.

Stroke prevention in elderly patients with atrial fibrillation: challenges for anticoagulation.

Elderly patients with atrial fibrillation (AF), who constitute almost half of all AF patients, are at increased risk of stroke. Anticoagulant therapies, especially vitamin K antagonists (VKA), reduce the risk of stroke in all patients including the elderly but are frequently under-used in older patients. Failure to initiate VKA in elderly AF patients is related to a number of factors, including the limitations of current therapies and the increased risk for major haemorrhage associated with advanced age and anticoagulation therapy. Of particular concern is the risk of intracranial haemorrhages (ICH), which is associated with high rates of mortality and morbidity. Novel oral anticoagulant agents that are easier to use and might offer similar or better levels of stroke prevention with a similar or reduced risk of bleeding should increase the use of antithrombotic therapy in the management of elderly AF patients. Amongst these new agents, the recently approved direct thrombin inhibitor dabigatran provides effective stroke prevention with a significant reduction of ICH, and enables clinicians to tailor the dose according to age and haemorrhagic risk.

Thromboembolism prophylaxis with dabigatran leads to lower perioperative blood loss than with dalteparin in primary knee arthroplasty.

INTRODUCTION: Low-molecular-weight heparins (LMWH) are commonly used in thrombosis prophylaxis after total knee arthroplasty. In contrast to LMWH, dabigatran etexilate is an oral and direct acting anticoagulant. The hypothesis of the present study was that blood loss occurring in total knee arthroplasty (TKA) is not greater after dabigatran etexilate than after dalteparin. METHOD: All patients suffering from primary arthrosis of knee joint that had received a total knee arthroplasty were included in this retrospective case-control study. Two groups were formed (dalteparin versus dabigatran etexilate) and the perioperative blood loss was compared using the formula of Nadler (V = EBV × ln (Hct(0)/Hct(1)) [V = blood loss (l); EBV = blood volume (l); Hct(0) = preoperative haematocrit; Hct(1) = haematocrit on the first postoperative day]. PATIENTS: A total of 155 patients, 61 men and 94 women, were included. The calculated blood loss differed significantly between the two groups. The blood loss was on average 1.5 ± 0.58 l [0.32-2.9 l] in the dalteparin group, compared with 1.3 ± 0.63 l [0.29-4.31 l] in the dabigatran etexilate group (p < 0.01). None of the patients of both observed groups showed clinical signs of thrombosis or pulmonary artery embolism. RESULTS: Dabigatran etexilate showed a lower perioperative blood loss than dalteparin by comparable safety of both drugs. CONCLUSION: Whether the timing of administration or pharmacological factors were responsible for this cannot be explained by our study.

New oral anticoagulants for venous thromboembolism prophylaxis in orthopaedic surgery.

Anticoagulant drugs reduce the risk of venous thromboembolic events after total hip and knee arthroplasty. However, the use of current drugs, such as low-molecular-weight heparins, is hampered by their subcutaneous administration. The use of a vitamin K antagonist, such as warfarin, is hampered by the required routine coagulation monitoring and dose titration to provide effective anticoagulation without an increased risk of bleeding. Numerous possible food and drug interactions must also be considered. New classes of oral anticoagulant agents have been developed that have a fixed dose, do not require coagulation monitoring, do not have food and drug interactions, and demonstrate similar or better efficacy and safety profiles when compared with current agents.

Dabigatran etexilate: a novel oral thrombin inhibitor for thromboembolic disease.

OBJECTIVE: To evaluate the efficacy and safety of dabigatran etexilate, approved by the Food and Drug Administration (FDA) in October 2010 for the prevention of cardioembolic stroke in patients with atrial fibrillation; potential off-label use is treatment and prevention of venous thromboembolic disorders. DATA SOURCES: Literature was accessed through MEDLINE (1977-April 2011) and International Pharmaceutical Abstracts (1977-April 2011) using the terms dabigatran, dabigatran etexilate, BIBR 1048, direct thrombin inhibitor, anticoagulant, and thromboembolism. In addition, US government Web sites, including clinicaltrials.gov and fda.gov, were reviewed for pertinent information. Lastly, reference citations from publications identified in the initial search were reviewed. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data sources were evaluated. For the evaluation of clinical efficacy and safety, only Phase 2 and 3 studies are included in this review. DATA SYNTHESIS: In 6 published Phase 3 trials to date, dabigatran has exhibited a similar efficacy and safety profile to that of comparator drugs, including dose-adjusted warfarin and enoxaparin, at various dosages. In the largest of these trials, RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy), dabigatran was at least as effective as dose-adjusted warfarin in reducing stroke or systemic embolism. Overall bleeding risks were similar; however, dabigatran may be associated with a lower incidence of intracranial bleeding and hemorrhagic stroke but a higher incidence of gastrointestinal bleeding. Although dabigatran is not approved for venous thromboembolism (VTE) prevention or treatment, results of the RE-MODEL and RE-NOVATE trials suggest similar efficacy to once-daily dosing of enoxaparin 40 mg but inferior efficacy to the FDA-approved twice-daily dosing of enoxaparin 30 mg in the RE-MOBILIZE trial. CONCLUSIONS: Dabigatran is an effective and safe alternative to oral vitamin K antagonists for stroke prevention in patients with nonvalvular atrial fibrillation, with fewer drug interactions and monitoring requirements. Additionally, dabigatran may be a viable alternative to enoxaparin in VTE prevention and warfarin in VTE treatment, although current trial data are limited.

Dabigatran for stroke prevention in atrial fibrillation: from RE-LY to daily clinical practice.

OBJECTIVE: The RE-LY trial has shown that the oral direct thrombin inhibitor dabigatran etexilate is a valid replacement for oral anticoagulation with vitamin K antagonists (VKA) in patients with atrial fibrillation at thromboembolic risk. After a decade of failures, these results signify a breakthrough in anticoagulation management. This article summarizes the available evidence from the perspective of the practicing clinician: do the results apply to all patients with AF? And what considerations should we make when prescribing this new oral anticoagulant? METHODS AND RESULTS: We review the trials searching for oral alternatives to VKA therapy, with emphasis on the RE-LY data.We have integrated available interaction data, and data on how to deal with side effects and (bleeding) complications with the direct thrombin inhibitor dabigatran etexilate. CONCLUSIONS: abigatran etexilate is a viable alternative to VKA, improving efficacy and safety in many respects, for many patients, and likely preferred by most patients themselves. Choosing the dose should be based on patient-specific factors. These include the presence of coronary artery disease (with potential requirement of concomitant aspirin +/- clopidogrel), decreased renal function, age, low body weight, administration of otherAF drugs or P-glycoprotein inhibitors, a history of gastro-intestinal bleeding, and patient compliance.