Specific Antidote For Dabigatran Research Articles

Reversing anticoagulation in the hemorrhaging patient.

Anticoagulants in general, but especially the relatively new direct oral anticoagulants and platelet inhibitors, pose a great challenge for physicians in the hemorrhaging patient. The aim of the present review is to provide an overview on recent studies dealing with the reversal of anticoagulation in the hemorrhaging patient and to describe our therapeutic emergency strategy for those patients. A specific antidote for dabigatran is already on the market and antidotes for the direct and indirect factor Xa inhibitors are in development. Moreover, bleeding under platelet inhibitors remains critical with very little evidence on effective reversal strategies. To reverse anticoagulation in the hemorrhaging patient, specific antidotes should be the first option if available, followed by four-factor prothrombin complex concentrate (PCC), activated PCC and recombinant activated factor seven as the emergency strategy. Fibrinogen concentrate, antifibrinolytics and oral charcoal, respectively, can be considered as an additional measure. Massive blood loss and thrombocytopenia should be treated independently according to the respective, local guidelines for (massive) transfusion of blood and blood products.

Management of bleeding associated with direct oral anticoagulants: update on reversal strategies

Direct oral anticoagulants (DOACs), including the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban have at least comparable efficacy as vitamin K antagonists along with a better safety profile, reflected by a lower incidence of intracranial hemorrhage. Specific reversal agents have been developed in recent years. Namely, idarucizumab, a specific antidote for dabigatran, is currently approved in most countries. Andexanet, which reverses factor Xa inhibitors, has been recently approved by the FDA, and ciraparantag, a universal antidote targeted to reverse all DOACs, is still under investigation. In this review we provide an update on the pharmacology of DOACs, the risk of hemorrhagic complications associated with their use, the measurement of their anticoagulant effect and the reversal strategies in case of DOAC-associated bleeding.

Idarucizumab: What Should We Know?

Idarucizumab, a humanized monoclonal antibody fragment acting as a specific antidote for dabigatran, is approved for reversing the dabigatran-associated possible bleeding from critical sites or bleeding persisting despite local post-procedure haemostasis. Moreover, it can also be applied to reverse the dabigatran anticoagulant activity in emergency surgery or in other invasive procedure at high risk of bleeding. In this study, we discuss idarucizumab in light of the available literature data by conducting extensive research in the PubMed, EMBASE and Cochrane Library on the topic, using idarucizumab, dabigatran and their combinations as Mesh terms, and focusing on high impact investigations. Several studies have demonstrated the capacity of idarucizumab to reverse laboratory measures of dabigatran-associated coagulopathy, however its efficacy and safety in real world patients are still not very clear because of the scarcity of available data which should be assessed with an extensive post market surveillance. The introduction of idarucizumab as dabigatran antidote in clinical practice represents a useful tool for clinicians. The possibility to rapidly restore the anticoagulation activity of dabigatran makes its use simpler and more manageable.

Direct oral anticoagulants (DOAC) – Management of emergency situations

SummaryThe worldwide increase in the aging population and the associated increase in the prevalence of atrial fibrillation and venous thromboembolism as well as the widespread use of direct oral anticoagulants (DOAC) have resulted in an increase of the need for the management of bleeding complications and emergency operations in frail, elderly patients, in clinical practice. When severe bleeding occurs, general assessment should include evaluation of the bleeding site, onset and severity of bleeding, renal function, and concurrent medications with focus on anti-platelet drugs and nonsteroidal anti-inflammatory drugs (NSAID). The last intake of the DOAC and its residual concentration are also relevant. The site of bleeding should be immediately localized, anticoagulation should be interrupted, and local measures to stop bleeding should be taken. In life-threatening bleeding or emergency operations immediate reversal of the antithrombotic effect may be indicated. If relevant residual DOAC-concentrations are expected and surgery cannot be postponed, prothrombin complex concentrate (PCC) and/or a specific antidote should be given. While idarucizumab, the specific antidote for dabigatran, has been recently approved for clinical use, the recombinant factor X protein andexanet alfa, an antidote for the reversal of inhibitors of coagulation factor Xa, and ciraparantag, a universal antidote, are not available. Future cohort studies are necessary to assess the efficacy and safety of specific and unspecific reversal agents in “real-life” conditions. This was the rationale for introducing the RADOA-registry (RADOA: Reversal Agent use in patients treated with Direct Oral Anticoagulants or vitamin K antagonists), a prospective non-interventional registry, which will evaluate the effects of specific and unspecific reversal agents in patients with life-threatening bleeding or emergency operations either treated with DOACs or vitamin K antagonists.

Idarucizumab, a Specific Antidote for Dabigatran, Cross-Reacts with Melagatran and May Also Interact with Other Benzamidine-Containing Compounds

Introduction: Dabigatran etexilate is a pro-drug which is used to prevent embolic stroke in patients with atrial fibrillation. This oral anticoagulant is also approved for other indications in Europe. As with all anticoagulants, there is a potential for serious hemorrhage with dabigatran usage which may require antidotes to control bleeding. Idarucizumab is an anti-dabigatran Fab fragment (Boehringer-Ingelheim) that binds to the benzamidine group on dabigatran and inhibits its anti-thrombin activity. Idarucizumab has recently been approved by the US FDA for the control of bleeding associated with dabigatran.Materials and Methods: Such antithrombin agents as argatroban, melagatran, hirudin, and bivalirudin, human antithrombin, thrombomodulin, heparin cofactor II, and heparin-AT complex were commercially obtained. Anti-factor Xa agents (rivaroxaban, apixaban and DX-9065a were also obtained from various sources To test the specificity of the inhibitory effects of idarucizumab, each of these agents were supplemented to whole blood and citrated plasma at concentrations ranging from 0.1 to 100 µg/mL. Idarucizumab was added to each mixture at a concentration of 1 mg/mL and anticoagulant activities were assessed using PT, aPTT, thrombin time and chromogenic anti-IIa/Xa and flurometric thrombin generation assays.Results: Idarucizumab itself did not produce any anticoagulant effects on whole blood or plasma clotting profile. However it showed a slight procoagulant effect in the whole blood and plasma based assays. It produced a strong concentration dependant inhibition of both dabigatran and melagatran. The antibody showed strong specificity for the inhibition of dabigatran amd melagatran and did not affect the anticoagulant and other effects of the other synthetic and natural thrombin and FXa inhibitors. The prolongation of the PT, APTT and thrombin time by melagatran was completely inhibited by idarucizumab. Idarucizumab more effectively inhibited the prolongation of thrombin time by dabigatran than the prolongation induced by melagatran.Discussion: The cross-reactivity of idarucizumab with melagatran may result from the presence of a common benzamidine pharmacophore which is present in both of these anticoagulant agents. Since the benzamidine pharmacophore is present in a number of serine protease inhibitors as well as drugs such as pentamidine, propamidine and dibromopropamidine. These observations suggest that simultaneous administration of idarucizumab may compromise the pharmacodynamics profile of benzamidine derived drugs such as the anti-malarials, anti-psychotic, anti-fungal and other compounds. Thus there is a need for a systemic screening of idarucizumab for its potential interactions with drugs containing benzamidine based therapeutic agents. DisclosuresNo relevant conflicts of interest to declare.

Idarucizumab, a Specific Antidote for Dabigatran: Immediate, Complete and Sustained Reversal of Dabigatran Induced Anticoagulation in Elderly and Renally Impaired Subjects

IntroductionOral anticoagulation is an effective therapy to prevent and treat thromboembolic events. So far, Vitamin K antagonists have been the main drug of choice. Recently, the advent of the direct oral anticoagulants (DOAC) has changed medical practice significantly; nevertheless all anticoagulants are associated with an increased risk of bleeding. Bleeding management can be achieved through established therapies; however specific antidotes are not yet available for these agents to further facilitate patient management in cases needed. Previously the dabigatran antidote (idarucizumab) has demonstrated immediate, complete and sustained reversal of dabigatran induced anti-coagulation in healthy male volunteers. In the present study it was determined whether and to what extent doses of up to 5 g idarucizumab would reverse the anticoagulant effects of dabigatran in male and female healthy mid-aged, elderly and renally impaired volunteers. In addition, it was tested whether oral intake of dabigatran etexilate 24 hrs after idarucizumab treatment could restore dabigatran related anticoagulation. It was further tested if a second administration of idarucizumab 2 months later was safe and well tolerated.MethodsSafety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of idarucizumab were investigated in a randomized, double-blind, placebo controlled two-way cross-over study in 46 male and female volunteers. Dabigatran etexilate (DE), 220 mg bid in healthy subjects and 150 mg bid in subjects with mild or moderate renal impairment (CLCR60 to <90 or 30 to <60 [mL/min], respectively) was given over 4 days to achieve the steady state conditions. Idarucizumab doses of 1 g, 2.5 g, 5 g or 5 g given as 2x2.5 g one hour apart were administered as 5 min i.v. infusion 2 hrs after the last dose of DE. Concentrations of unbound dabigatran were determined as a measure of pharmacologically active dabigatran. The anticoagulant effect of dabigatran and its reversal were assessed by coagulation time measurements, including diluted Thrombin Time (dTT, Hemoclot® DTI assay), Ecarin Clotting Time (ECT) and activated Partial Thromboplastin Time (aPTT).ResultsAll administered doses of idarucizumab were safe and well tolerated. PK measurements of unbound dabigatran indicated that idarucizumab binding and thus reversal of the anticoagulant effect of dabigatran occurred immediately after end of infusion. Prolongation of clotting times induced by dabigatran was reversed to baseline at the end of the 5 minute infusion of the antidote. This was consistently demonstrated by all clotting assays. Sustained reversal over the entire observation period was observed for idarucizumab doses of 2.5 g, 5 g and 2x2.5 g. For the 1g dose, there was partial return of dabigatran induced anticoagulation around 2-4 hours after i.v. infusion. Also a second administration of idarucizumab (two months after the first) was safe and resulted in complete reversal. In addition, PD and PK measurements at selected time points and in comparison to placebo treatment confirmed that effective dabigatran anticoagulation could be re-established 24 hours after administration of idarucizumab.ConclusionsThe dabigatran antidote, idarucizumab, was well tolerated under all conditions tested. The administration of 5 g or 2x2.5 g led to sustained reversal of dabigatran induced anticoagulation in male and female subjects of different age and renal function. In addition, idarucizumab administered 2 months apart achieved the same degree of reversal. Dabigatran anticoagulation could be re-established 24 hrs after idarucizumab dosing. These results support the use of a total dose of 5 g idarucizumab as an effective dose in further clinical testing. DisclosuresGlund:Boehringer Ingelheim: Employment. Off Label Use: Idarucizumab, a specific antidote for dabigatran, is in clinical development.. Stangier:Boehringer Ingelheim: Employment. Schmohl:Boehringer Ingelheim: Employment. Moschetti:Boehringer Ingelheim: Employment. Haazen:SGS Life Science Services (contracted by Boehringer Ingelheim to conduct the study): Employment. De Smet:SCS Boehringer Ingelheim Comm. V.: Employment. Gansser:Boehringer Ingelheim: Employment. Norris:Boehringer Ingelheim: Employment. Lang:Boehringer Ingelheim: Employment. Reilly:Boehringer Ingelheim: Employment.

Idarucizumab Fully Restores Dabigatran-Induced Alterations on Platelet and Fibrin Deposition on Damaged Vessels: Studies in Vitro with Circulating Human Blood

BACKGROUNDDespite the proven efficacy and safety profile of dabigatran as compared to warfarin, bleeding remains a concern as with all anticoagulants and the reversal of dabigatran’s anticoagulant effect for emergency procedures remains controversial. Recently, idarucizumab, a specific antidote for dabigatran, has been functionally characterized and its efficacy demonstrated in animal models and healthy volunteer studies. AIMSWe explored the effects of dabigatran on hemostasis in human blood focusing on possible interference with platelet and coagulation responses to vessel injury under flow conditions. We also compared the potential efficacy of idarucizumab with procoagulant strategies such as prothrombin complex concentrates (PCC), activated PCC (aPCC) or rFVIIa at reversing the antithrombotic action of dabigatran to better understand local processes in response to injury. METHODSConcentrations of dabigatran equivalent to the Cmax reported at steady state after therapy with 150 mg twice daily (184 ng/mL) were added in vitro to blood aliquots from 11 healthy donors. Whole blood samples were used to evaluate modifications in different coagulation biomarkers: 1) fibrin and platelet deposition on damaged vascular segments with whole blood under flow conditions at a shear rate of 600 s-1, 2) dynamics of thrombin generation (TG) in plasma using a fluorogenic assay (Technothrombin TGA) and 3) viscoelastic parameters of clot formation in whole blood using by thromboelastometry (ROTEM) The efficacy of specific reversal with idarucizumab 0.3, 1 and 3 mg/mL was compared with that of non specific procoagulant concentrates such as aPCC 25 and 75 IU/kg, PCC 70 IU/kg, or rFVIIa 120 µg/kg. RESULTSDabigatran (184 ng/mL) caused a pronounced 85% reduction of fibrin coverage on the damaged vessel from 67.2±9.8 to 9.5±1.3 % (p<0.01) and a moderate 35% reduction of platelet deposition from 25.9±2.7 to 16.9±2.9 % (p<0.01). Dabigatran also altered dynamics of TG with a prolongation of the lag-phase and a reductions in the maximal thrombin peak and potential of thrombin generation (p<0.01). In ROTEM, dabigatran significantly prolonged clotting time to 352±60 sec (p<0.01) and clot formation time to 312±76 sec (p<0.05). Idarucizumab completely reversed the alterations in all different biomarkers induced by dabigatran. Additionally, fibrin coverage and platelet deposition were restored to baseline values in flow studies. TG and ROTEM parameters also returned to normal values after idarucizumab. Reversal strategies with aPCC or PCC normalized and even over-compensated alterations in TG kinetics and partially improved alterations in ROTEM parameters caused by dabigatran. Interestingly, aPCC and PCC moderately improved the alteration in fibrin deposition caused by dabigatran in flow studies (15.7±8.2, 29.3±14.5, and 15.2±3.7 %, respectively for aPCCs 25, 75 or PCCs 70 IU/kg). However, levels of fibrin formation did not return to baseline values before dabigatran (67.2±32.5 %). rFVIIa showed only moderate effects on some of the biomarkers evaluated, though values were never restored to the baseline. CONCLUSIONSDabigatran (184 ng/mL) added to blood from healthy volunteers caused evident alterations in hemostasis parameters related to its recognized anticoagulant action. Procoagulant concentrates significantly compensated for the overall anti-hemostastic action of dabigatran. Overall, 75 U/kg aPCC seemed the more efficient nonspecific reversal therapy. In clear contrast with non specific procoagulant strategies, idarucizumab, the specific antidote to dabigatran completely reversed all alterations in coagulation parameters evaluated in circulating human blood and in assay systems.(Supported by SAF 2011-2814 and PI13/00517, Spanish Gov & FEDER) Disclosuresvan Ryn:Boehringer Ingelheim Pharma: Employment. Escolar:Boehringer Ingelheim Pharma: Investigator Sponsored Research Funding Other.

A specific antidote for dabigatran: functional and structural characterization

AbstractDabigatran etexilate is a direct thrombin inhibitor and used widely as an anticoagulant for the prevention of stroke in patients with atrial fibrillation. However, anticoagulation therapy can be associated with an increased risk of bleeding. Here, we present data on the identification, humanization, and in vitro pharmacology of an antidote for dabigatran (aDabi-Fab). The X-ray crystal structure of dabigatran in complex with the antidote reveals many structural similarities of dabigatran recognition compared with thrombin. By a tighter network of interactions, the antidote achieves an affinity for dabigatran that is ∼350 times stronger than its affinity for thrombin. Despite the structural similarities in the mode of dabigatran binding, the antidote does not bind known thrombin substrates and has no activity in coagulation tests or platelet aggregation. In addition we demonstrate that the antidote rapidly reversed the anticoagulant activity of dabigatran in vivo in a rat model of anticoagulation. This is the first report of a specific antidote for a next-generation anticoagulant that may become a valuable tool in patients who require emergency procedures.