Oral Direct Thrombin Inhibitor Dabigatran Research Articles

Thrombin Generation Is Differentially Affected By Anticoagulants in Patients with Acute Lymphoblastic Leukemia - an Ex-Vivo Study

Background: Venous thromboembolism (VTE) is a frequent complication in patients with acute lymphoblastic leukemia (ALL). Low molecular weight heparin (LMWH) reduces the risk of VTE in ALL, but is not well tolerated in children. VTE rates remain unacceptably high in adults despite LMWH prophylaxis. Thus, novel strategies for VTE prevention are warranted. In the primary analysis of the PREVAPIX-ALL trial there was no statistically significant reduction in VTE among children treated with the oral factor Xa inhibitor, apixaban, compared to no anticoagulation (AC). Comparative data on activity of different anticoagulants are needed to guide planning of VTE prophylaxis trials. Aims: To characterize and compare the ex-vivo effect of LMWH (enoxaparin), oral direct factor Xa inhibitors (apixaban, rivaroxaban) and oral direct thrombin inhibitor (dabigatran etexilate) in ALL patients' samples using thrombin generation (TG). Methods: A prospective observational cohort study of 46 children with newly-diagnosed ALL, treated with the L-asparaginase (ASP)-based BFM protocol, at a tertiary medical center. Patients on therapeutic-dose AC at baseline were excluded. Blood samples were drawn before ASP treatment (ALL-Day0) and 7 days after (ALL-Day7). Normal pooled plasma (NP) was collected from healthy adult volunteers. Samples were spiked ex-vivo with enoxaparin [0.2 U/mL], apixaban [39 ng/mL], rivaroxaban [39 ng/mL] and dabigatran [150 ng/mL] or vehicle (i.e., control). AC concentrations chosen based on 50% peak reduction (for Xa inhibitors) or 200% LT prolongation (for dabigatran) in NP. Subsequently, TG was performed initiated using 5 pM tissue factor in the presence of 4 µM phospholipids using Calibrated Automated Thrombogram method in these samples. Results are expressed as peak height (PH) and lag time (LT) and relative reduction or prolongation (% difference in PH or LT, respectively) in plasma samples spiked with anticoagulants compared to control. Reduction in PH reflects enoxaparin, apixaban and rivaroxaban activity, while LT prolongation indicates dabigatran activity. This report focuses on measures reflecting the activity of each drug. Descriptive statistics were used to show the median [interquartile range (IQR)] for continuous variables and percentages for categorical data. T-Test / Mann-Whitney U test and paired T-test / Wilcoxon test used to compare between paired and non-paired samples, respectively. Results: Selected sample characteristics are as follows: median age, 7.75 years [IQR 3.73-11.93]; 19 (41%) females; median BMI, 16.8 [IQR 15.5-19.9]; B-cell precursor immunophenotype in 33 (71.7%) and T-cell in 13 (28.3%); prior VTE in 1 (2%). Median PH [IQR] in control samples (without AC) was 256.6 [252.6-265.3] nmol/l, 396.0 [347.2-464.7] nmol/l and 354.4 [307.1-407.4] nmol/l in NP, ALL-Day0 and ALL-Day7 respectively. Median LT [IQR] in control samples was 2.7 [2.5-2.83] nmol/l, 1.8 [1.7-2.3] nmol/l and 1.7 [1.6-2] nmol/l in NP, ALL-Day0 and ALL-Day7 respectively. Median % differences in PH and LT between samples spiked with different anticoagulants and controls are shown in Figure 1A and Figure 1B, respectively. Enoxaparin, apixaban and rivaroxaban reduced PH in NP, ALL-Day0 and ALL-Day7 samples (p<0.0005). There was less reduction in PH with enoxaparin, apixaban and rivaroxaban in ALL-Day0 samples than in NP (p=0.029, p<0.0005, p<0.0005 respectively), suggesting reduced anticoagulant activity in ALL patients compared to subjects without ALL. LT was prolonged with dabigatran in NP, ALL-Day0 and ALL-Day7 samples (p<0.05). Dabigatran resulted in a similar LT prolongation in ALL-Day0 and NP (p=0.677), suggesting a preserved AC effect in ALL. There was less LT prolongation in ALL-Day7 (134% [123-175%] than in ALL-Day0 (180% [134-238]; p=0.031). This reflects an ongoing dabigatran effect after ASP, albeit to a lesser degree. Conclusions: Our ex-vivo results suggest limited anticoagulant activity of enoxaparin and lack of anticoagulant activity of apixaban and rivaroxaban (both factor Xa inhibitors) in preventing VTE in ALL, in line with prior clinical data. In contrast, dabigatran etexilate, an oral direct thrombin inhibitor not previously tested in ALL, exhibited preserved anticoagulant activity in ALL patients, even after exposure to ASP. This may suggest that dabigatran should be investigated in clinical studies for the unmet need of VTE prophylaxis in ALL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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.

Direct-acting oral anticoagulants: pharmacology, indications, management, and future perspectives.

In recent years, several direct-acting oral anticoagulants (DOAC) have become available for use in Europe and other regions in indications related to prophylaxis and treatment of venous and arterial thromboembolism. They include the oral direct thrombin inhibitor dabigatran etexilate (Pradaxa, Boehringer Ingelheim) and the oral direct FXa inhibitors rivaroxaban (Xarelto, Bayer HealthCare), apixaban (Eliquis, Bristol-Myers Squibb), and edoxaban (Lixiana/Savaysa, Daiichi-Sankyo). The new compounds have a predictable dose response and few drug-drug interactions (unlike vitamin k antagonists), and they do not require parenteral administration (unlike heparins). However, they accumulate in patients with renal impairment, lack widely available monitoring tests for measuring its anticoagulant activity, and no specific antidotes for neutralization in case of overdose and/or severe bleeding are currently available. In this review, we describe the pharmacology of the DOAC, the efficacy, and safety data from pivotal studies that support their currently approved indications and discuss the postmarketing experience available. We also summarize practical recommendations to ensure an appropriate use of the DOAC according to existing data. Finally, we discuss relevant ongoing studies and future perspectives.

Specific antidotes in development for reversal of novel anticoagulants: a review.

In the last decade, several direct oral anticoagulants (DOAC; dabigatran, rivaroxaban, apixaban, edoxaban) have been marketed for prophylaxis and/or treatment of thromboembolism without having specific antidotes available for their reversal. Current management of bleeding associated to DOAC includes the removal of all antithrombotic medications and supportive care. Non-specific procoagulant agents (prothrombin complex concentrates and activated factor VIIa) have been used in case of serious bleeding. Currently, some specific antidotes for the DOAC are under development. Idarucizumab (BI 655075; Boehringer Ingelheim) is a fragment of an antibody (Fab), which is a specific antidote to the oral direct thrombin inhibitor dabigatran. Andexanet alfa (r-Antidote, PRT064445; Portola Pharmaceuticals) is a truncated form of enzymatically inactive factor Xa, which binds and reverses the anticoagulant action of the factor Xa inhibitors (e.g.: rivaroxaban, apixaban and edoxaban). Aripazine (PER-977, ciraparantag; Perosphere Inc.) is a synthetic small molecule (~500 Da) that reverses oral dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH in vivo. These antidotes could provide an alternative for management of life-threatening bleeding events occurring with the above-mentioned anticoagulants. In addition, the specific antidote anivamersen (RB007; Regado Biosciences Inc.) is an RNA aptamer in clinical development to reverse the anticoagulant effect of the parenteral factor IXa inhibitor pegnivacogin, which is also in development. This anticoagulant-antidote pair may provide an alternative in situations in which a fast onset and offset of anticoagulation is needed, like in patients undergoing cardiac surgery with extracorporeal circulation, as an alternative to the heparin/protamine pair. This patent review includes a description of the pharmacological characteristics of the novel specific antidotes, the available results from completed non-clinical and clinical studies and the description of ongoing clinical trials with the new compounds.

Effects of thromboembolism prophylaxis with dabigatran on perioperative blood loss and wound secretion in primary hip arthroplasty.

Low-molecular-weight heparins (LMWH), e.g. enoxaparin, represent the standard thromboprophylactic agents in Europe after total hip replacement. The oral direct thrombin inhibitor dabigatran etexilate provides comparable effectiveness and safety. The present study aimed to evaluate the influence of dabigatran etexilate on perioperative blood loss and wound secretion in total hip arthroplasty compared to enoxaparin. Patients receiving primary total hip replacement between January and June 2009 were included. The association between thromboembolism prophylaxis with dabigatran etexilate or enoxaparin and the perioperative blood loss was investigated. The effective blood loss (EBL) was calculated taking blood transfusions and the difference between preoperative haemoglobin and haemoglobin on the day of discharge into account. Additional comparison of wound secretion depending on thromboprophylactic agents was performed in a separate, prospectively collected patients' population. Statistical analysis was performed with χ<formula> ^{2}</formula>-Test, Student's t-test or Mann-Whitney U-test. Statistical significance was considered at p < 0.05. 198 patients (111 women, 87 men) with primary total hip arthroplasty were enrolled. Patients' mean age was 63.0 ± 11.9 years. Thromboembolism prophylaxis was performed in 111 patients (56.1%) with dabigatran etexilate, 87 patients (43.9%) received enoxaparin. No significant differences concerning EBL and wound secretion were found between both study groups. In the dabigatran etexilate group the EBL was 1.66 ± 0.56 l compared to 1.77 ± 0.65 l in patients with enoxaparin. Dabigatran etexilate can safely be used for thromboembolism prophylaxis after primary total hip replacement without an increased risk for perioperative blood loss and prolonged wound secretion.

On the monitoring of dabigatran treatment in “real life” patients with atrial fibrillation

IntroductionThe oral direct thrombin inhibitor dabigatran is increasingly used to prevent thromboembolic stroke in patients with atrial fibrillation (AF). Routine laboratory monitoring is currently not recommended, but measurements of dabigatran and/or its effect are desirable in certain situations. We studied dabigatran exposure and compared different tests for monitoring of dabigatran in a real-life cohort of AF patients. Material and methodsNinety AF patients (68±9years, 67% men, mean CHADS2 score 1.5) were treated with dabigatran 150 (n=73) or 110mg BID (n=17). Trough plasma concentrations of total and free dabigatran by liquid chromatography-tandem mass-spectrometry (LC-MS/MS) were compared to indirect measurements by Hemoclot thrombin inhibitors (HTI) and Ecarin clotting assay (ECA), as well as PT-INR and aPTT. ResultsTotal plasma dabigatran varied 20-fold (12–237ng/mL with 150mg BID) and correlated well with free dabigatran (r2=0.93). There were strong correlations between LC-MS/MS and HTI or ECA (p<0.001) but these assays were less accurate with dabigatran below 50ng/mL. The aPTT assay was not dependable and PT-INR not useful at all. There were weak correlations between creatinine clearance (Cockcroft-Gault) and LC-MS/MS, HTI and ECA (p<0.001 for all). A high body weight with normal kidney function was associated with low dabigatran levels. ConclusionsHTI and ECA reflect the intensity of dabigatran anticoagulation, but LC-MS/MS is required to quantify low levels or infer absence of dabigatran. Most real life patients with a normal creatinine clearance had low dabigatran levels suggesting a low risk of bleeding but possibly limited protection against stroke.

Análise da Revisão Cochrane: Inibidores da Trombina versus Antagonistas da Vitamina K na Prevenção do Acidente Vascular Cerebral em Doentes com Fibrilhação Auricular Não-Reumática. Cochrane Database Syst Rev. 2014,3:CD009893.

Ischemic stroke is one of the most important complications of lone (non-valvular) atrial fibrillation. Its prevention is usually accomplished through oral anticoagulation. Until a few years ago warfarin was the most used agent, but recently two new pharmacologic classes have been introduced for stroke prevention in these patients: oral direct thrombin inhibitors (dabigatran and ximelagatran) and oral factor Xa inhibitors (rivaroxaban, apixaban and edoxaban). In this systematic review, oral direct thrombin inhibitors were compared with warfarin for efficacy and safety. The results indicate that there is no difference in terms of efficacy (except dabigatran 150 mg BID). Oral direct thrombin inhibitors presented less hemorrhages but increased treatment withdrawal due to adverse side-effects (the authors performed post-hoc analyses excluding ximelagatran because this drug was withdrawn from the market owing to safety concerns). There was no difference in terms of mortality between the agents.

Koncept modifikacije doze oralnih antikoagulantnih lekova radi smanjenja rizika od hemoragijskih komplikacija - kako odabrati pravu dozu?

Variable intensity of anticoagulant effect with oral vitamin K antagonists (VKA), which may be aggravated by diet, alcohol consumption and concomitant drug therapy necessitates regular laboratory monitoring of anticoagulant intensity and VKA dose adjustments. Frequent oscillations of the International Normalized Ratio (INR) values outside the therapeutic range and resultant low Time in therapeutic Range (TTR ) increase the risk of both thromboembolic and bleeding events, and many patients eventually stop taking VKA after some time. Those were the reasons that prompted the search for alternative oral anticoagulant drugs. It was never about efficacy, but a more convenient (and possibly safer) therapy has been searched for, which would allow for a fixed dosing without the need for routine laboratory monitoring of anticoagulant effect due to stable, dose-dependent anticoagulation. Now it seems that these aims have been achieved, at least partly. Since recently, we have oral anticoagulant drugs which are much safer than VKAs, particularly in terms of significantly reduced risk of the most serious, often fatal haemorrhagic complication of oral anticoagulant therapy - intracerebral haemorrhage. Efficacy of these 'new' drugs - non-vitamin K oral anticoagulants (NOAC s) is more or less similar to the efficacy of VKAs, with no food interaction and fewer clinically relevant interactions with other drugs as compared to warfarin and other VKAs. However, with respect to the dosing of NOAC s and the need for blood analyses in patients taking a NOAC , available data suggest that we might not have not found the 'one size fits all' jacket yet. In essence, all randomized clinical trials comparing the efficacy and safety of oral direct factor Xa inhibitors versus warfarin for stroke prevention in AF (ROC KET-AF - rivaroxaban, ARI STOTL E - apixaban and ENGAG E-AF - edoxaban) also tested the NOAC dose modifications in relation to certain clinical characteristics of the patient, and the principles of dose modifications were pre-defined by the study protocol. In contrast, the RE-LY study tested efficacy and safety of the two doses of oral direct thrombin inhibitor dabigatran (110 mg or 150mg twice daily) with no dose modification, irrespective of the patient characteristics. In this commentary we discuss the principles of NOAC s individual dose selection for stroke prevention in AF in the context of recently published data.

Single-center Experience with Gastrointestinal Bleeding in Patients Taking the New Oral Direct Thrombin Inhibitor Dabigatran

Single-center Experience with Gastrointestinal Bleeding in Patients Taking the New Oral Direct Thrombin Inhibitor Dabigatran

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New oral anticoagulant drugs: real-world data.

Oral anticoagulants or ‘blood thinners’ were proposed in 400 BC during the time of Hippocrates [1]. The first paper entitled ‘Coumadin (warfarin) sodium – a new anticoagulant’ was published in 1956 [2]. Despite its limitations, coumadin stood the test of time. Ximelagatran, a very potent oral thrombin inhibitor, licensed in Europe for a short time, was later withdrawn in 2006 for concerns of causing hepatotoxicity [3].

Stroke Prevention in Atrial Fibrillation

Vitamin K antagonists (VKA) have been the primary anticoagulant for the past few decades, and to a lesser degree aspirin, in preventing thrombotic events from atrial fibrillation. In spite of our experience with warfarin over the years, its use has been limited by multiple challenges: its need for frequent international normalized ratio (INR) monitoring, its narrow therapeutic range, variation with metabolism, diet, and other medications, and the need for frequent dosage adjustment. With the advent of newer/novel oral anticoagulants such as oral direct thrombin inhibitors (dabigatran) and oral factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban), we are at the dawn of a new era in anticoagulation. Compared with VKAs, they do not need INR monitoring, have a rapid onset of action, are a fixed-dose therapy, and for unclear reasons, have been shown to cause significantly less intracranial hemorrhage than VKAs.

Moving Toward a More Ideal Anticoagulant: The Oral Direct Thrombin and Factor Xa Inhibitors

Thromboembolic diseases are common. Heparins and the vitamin K antagonists have been the mainstay of therapy for &gt; 60 years, but both classes of agents have limitations. The "ideal" anticoagulant should be as effective and safe as heparin and vitamin K antagonists but should also be available in both a parenteral and an oral formulation, have predictable pharmacokinetics, and lack significant toxicities unrelated to the anticoagulant activity. Moreover, it should target a specific coagulation factor and have an antidote that leads to rapid reversal. There are now agents that fulfill some of these criteria. Here we review the pharmacology and effectiveness of the oral activated factor X inhibitors rivaroxaban and apixaban and the oral direct thrombin inhibitor dabigatran. These agents have undergone extensive phase 3 testing and are currently approved for various indications in the United States, Canada, or Europe. Rivaroxaban is approved in the United States for VTE prevention after major orthopedic surgery and for stroke prevention in atrial fibrillation and is approved in Europe and Canada for secondary prevention of VTE. Apixaban is currently under review by the US Food and Drug Administration for stroke prevention and is approved in Europe for VTE prevention following major orthopedic surgery. Dabigatran is approved in the United States for stroke prevention in nonvalvular atrial fibrillation and is being reviewed for secondary prevention of VTE.

Practical issues, limitations, and periprocedural management of the NOAC’s

The recent introduction of new oral anticoagulants or novel target specific oral anticoagulants (TSOA's) is likely to have a major impact in the years ahead. Many large clinical trials have been published in the past few years showing these agents are generally safe and effective in several clinical settings including acute venous thromboembolic disease, prophylaxis in the postoperative setting, prevention of thromboembolism in patients with atrial fibrillation, and in the management of acute coronary syndromes. Reported rates of overall and intracranial bleeding are lower compared to oral vitamin K antagonists. Other major advantages of oral direct thrombin inhibitors (dabigatran) and Xa inhibitors (rivaroxaban and apixaban) include rapid onset and offset of action and predictable pharmacodynamics with relatively wide therapeutic window allowing for unmonitored drug use. The relatively short half-life, rapid onset of action, and predictable pharmacokinetics should simplify periprocedural use of these agents. In this review we focus on some practical issues related to TSOA's including some limitations, potential complications, considerations to be made for certain patient populations, periprocedural management and issues pertaining to transition to and from these novel agents.

Dabigatran Does Not Prolong the QT Interval with Supratherapeutic Exposure: a Thorough QT Study in Healthy Subjects

BackgroundDabigatran etexilate is a pro-drug of the oral reversible direct thrombin inhibitor dabigatran that interacts with the active site in the catalytic domain of the thrombin molecule.ObjectiveTo assess the electrophysiological effects of therapeutic and supratherapeutic doses of dabigatran etexilate in healthy subjects, a thorough QT study was performed.MethodsIn this single-centre, blinded, placebo- and active-controlled, four-period, crossover study, 40 healthy Caucasian subjects (20 women and 20 men) received single oral doses of dabigatran etexilate (150 mg and 600 mg), moxifloxacin 400 mg (positive control) or placebo, in a randomized order. Electrocardiogram (ECG) profiles were recorded at baseline and during the randomized study treatment in each period. The individually heart-rate–corrected QT interval (QTcI) was the primary parameter. The primary endpoint was the mean of these QTcI values obtained at 1.5, 2 and 3 h following study drug administration minus the mean of the time-matched QTcI values obtained at baseline day −1. The hypothesis tested was that the difference between each of the two doses of dabigatran etexilate (150 mg and 600 mg) and placebo, for the mean time-matched change from baseline (CfB) of QTcI between 1.5 and 3 h (the primary endpoint), was greater than or equal to 10 ms. Secondary endpoints were the time-matched CfB of QTcI between 0.5 and 24 h post-dose.ResultsAll subjects completed the study without premature discontinuation and all treatments were well tolerated. Following dabigatran etexilate administration, the mean values of the placebo-adjusted time-matched CfB of QTcI between 1.5 and 3 h post-dose were close to 0; the upper bound of the two-sided 90 % confidence interval (CI) was 1.4 ms for dabigatran etexilate 150 mg and 1.3 ms for dabigatran etexilate 600 mg. The placebo-adjusted time-matched CfB of QTcI remained close to 0 at all time points, and all 90 % CIs were between −5 ms and 5 ms, well below the pre-defined non-inferiority margin of 10 ms.ConclusionThis thorough QT study demonstrated that therapeutic and fourfold supratherapeutic doses of dabigatran etexilate do not prolong QT intervals.

Differences between indirect comparison studies of the oral anticoagulants for stroke prevention in atrial fibrillation: where do we go next?

Sir, Superior or equivalent efficacy and safety of the oral direct thrombin inhibitor dabigatran and the oral direct factor Xa inhibitors rivaroxaban and apixaban was shown for the prevention of ischaemic stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) in the RE-LY trial (dabigatran 150 and 110 mg bid), the ROCKET-AF trial (rivaroxaban 20 mg od) and the ARISTOTLE trial (apixaban 5 mg bid) vs. international normalized ratio (INR)-adjusted warfarin.1 Testa et al. 1 performed an indirect comparison of these anticoagulants in those patients by pooling the results of the control groups of the three studies treated with warfarin. In addition, they also pooled the results of new oral anticoagulants (NOAC) and compared them with the results they calculated for the pooled data of the warfarin groups of the three studies. Until mid-2012, …

Thrombin Inhibition Prevents Against Severe Atherosclerosis Progression in Prothrombotic Mice

AbstractAbstract 103 Background:Besides its well-known role in initiation and propagation of thrombus formation, thrombin may have multiple pro-atherogenic actions. Hypothesis:Pharmacologic thrombin inhibition attenuates the onset and progression of atherosclerosis and favors plaque stability in hypercoagulable mice prone to aggressive atherosclerosis development. Methods and Results:Hypercoagulability in TMPro/Pro:ApoE−/− mice resulted in severe atherosclerotic burden formation compared to ApoE−/− mice (389.1*103 μm2 vs. 187.0*103 μm2, p<0.0005). Pro-coagulant mice showed larger necrotic cores, decreased plaque collagen content, vast stenosis (up to 90%) and enhanced outward remodeling. Hypercoagulability markedly increased systemic and vascular inflammation, represented by significantly higher CXCL1, MCP-1 and G-CSF plasma levels, pronounced neutrophilia, enhanced Ly6G+ cells arrest to carotid plaques, increased neutrophil recruitment (IHC/Intravital Microscopy), massive intraplaque hemorrhage and spontaneous plaque ruptures. Genetically diminished prothrombin levels (FII-/WT:ApoE−/− mice) caused a significant decrease in atherosclerosis (72.5*103 μm2 vs. 128.4*103 μm2, p<0.01) with a pronounced stable phenotype with less/smaller necrotic cores, thicker fibrous caps and abundant collagen and vascular smooth muscle cell content. Ly6G+ cell intraplaque recruitment was reduced and white blood cell counts and IL-6 levels (3.8±1.66 vs. 8.8±5.34 pg/mL, p<0.05) were diminished compared to control mice. Remarkably, administration of the oral direct thrombin inhibitor Dabigatran etexilate or the anticoagulant activated protein C (APC) in TMPro/Pro:ApoE−/− mice reduced lesions formation by > 80%, suppressed leukocyte recruitment, enhanced plaque stability, whereas numerous pro-inflammatory cytokines were diminished to levels comparable to non-atherosclerotic mice. Conclusion:These data establish a pivotal role for thrombin generation in controlling the level of inflammation related to atherosclerosis development in ApoE−/− mice. The potential clinical impact of long term administration of novel classes of anticoagulants on atherosclerosis merits further study. Disclosures:Weiler:BloodCenter of Wisconsin: Patents & Royalties. van Ryn:Boehringer Ingelheim Pharma GmbH & Co KG: Employment.

Neue Antikoagulantien - die direkten Thrombininhibitoren

Direct thrombin-inhibitors inactivate not only free but also fibrin-bound thrombin. The group of parenteral direct thrombin-inhibitors includes the recombinant hirudins lepirudin and desirudin, the synthetic hirudin bivalirudin, and the small molecule argatroban. All these compounds do not interact with PF4/heparin-antibodies. Therefore, argatroban as well as bivalirudin are currently used to treat heparin-induced thrombocytopenia (HIT). The oral direct thrombin-inhibitor dabigatran etexilate is already licensed in many countries for the treatment of non-valvular atrial fibrillation. Dabigatran etexilate reveals a stable and predictable effect that allows a medication without dose adjustment or monitoring. The substance shows only few interactions with other drugs but strong inhibitors of p-glycoprotein can increase plasma levels of dabigatran substantially. After oral intake, the prodrug dabigatran etexilate is cleaved by esterase-mediated hydrolyses to the active compound dabigatran. Elimination of dabigatran is predominantly renal. Safety and efficacy of dabigatran etexilate were tested in an extensive clinical study program. Non-inferiority compared to current standard treatments was shown for prophylaxis of venous thromboembolic events after total knee and hip replacement, for stroke prevention in atrial fibrillation, and for treatment of acute venous thromboembolism. In daily practice, Dabigatran etexilate competes against the new direct factor Xa-inhibitors. In the absence of direct comparative clinical trials, it is not yet clear if one class of substances has distinct advantages over the other.

Direct thrombin inhibitors in cardiovascular disease

Limitations of commonly used anticoagulants, unfractionated heparin, low-molecular-weight heparin, and oral vitamin K antagonists have prompted the development of alternative therapies. Direct thrombin inhibitors are a new class of anticoagulants that bind directly to thrombin and inhibit its interaction with substrates. In this Review, we critically examine the evidence from randomized controlled trials for the efficacy and safety of the parenteral direct thrombin inhibitors bivalirudin and argatroban, and the novel oral direct thrombin inhibitor dabigatran etexilate, in cardiovascular and thrombotic disease.

A PRIMARY TEST OF COMBINED THROMBOPROPHYLAXIS AT LOWER EXTREMITIES ARTHROPLASTY: ASPECTS AND VARIANTS OF USAGE

Expansion of vein thrombosis and embolism remains a serious problem in traumatology and orthopedics up to the present day. Maintaining the balance between the efficiency of thromboprophylaxis and the danger of post operative hemorrhage can be achieved only when the prevention medication, its dose and the duration of use have been correctly chosen. An anticoagulant of the new generation (Pradaxa), per oral direct thrombin inhibitors dabigatran etexilate to the utmost complies with the above specified requirements that are why the authors decided in favor of its use in everyday clinical practice. A primary test for open use of dabigatran in 48 patients who underwent hip or knee arthroplasty has been carried out. Taking into account the highest risk of thromboembolic complications after large joints plasty, the method of mechanical prophylaxis DVT - electro neurostimulation of shin muscles has been introduced into clinical practice. According to the results of follow-up of the patients, who received different anticoagulants, the algorithm of an anticoagulant’s choice has been developed in various kinds of clinical situations with the possibility of changing injectable preparation to per oral forms. Convenience of per oral administration and predictability of dabigatran effect made it possible to provide consistency of hospital and out-patient stages of treatment, which also contributed to the reduction of thromboembolic complications, especially at an out-patient stage.