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Stroke and Transient Ischemic Attacks of the Brain and Eye
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Idarucizumab is a humanized monoclonal antibody fragment that specifically binds to dabigatran in a 1:1 molar ratio. It has an affinity for dabigatran that is ∼350 times greater than that of thrombin. It completely reversed the anticoagulant activity of dabigatran within minutes in almost all patients enrolled in the REVERSE-AD study who were taking dabigatran and presented with major or life-threatening bleeding, or with the necessity of emergency surgery.56 A total of 5 g of idarucizumab is administered intravenously in two bolus doses of 2.5 g no more than 15 minutes apart. Continued clinical and laboratory monitoring is recommended, since 5 g of idarucizumab may not completely neutralize exceptionally high levels of dabigatran (e.g. in case of overdose or renal insufficiency), and low levels of dabigatran may reappear after 12–24 hours. After 24 hours, dabigatran can be restarted if clinically indicated and feasible, with normal kinetics.
Neurosurgery: Cerebrovascular diseases
Published in Hemanshu Prabhakar, Charu Mahajan, Indu Kapoor, Essentials of Geriatric Neuroanesthesia, 2019
Paolo Gritti, Luigi Andrea Lanterna, Francesco Ferri, Carlo Brembilla, Ferdinando Luca Lorini
BP control is desirable in primary hypertensive ICH. It has been shown that intensive BP reduction within 3–6 h of onset of ICH to a systolic target of 110–139 mmHg does not result in a lower rate of death or disability than a standard reduction to a target of 140–179 mmHg, but the rate of renal adverse events within 7 days after randomization was significantly higher in the intensive-treatment group than in the standard-treatment group (28). Although platelet transfusion after ICH associated with antiplatelet drugs increases death and dependence at 3 months, spontaneous ICH associated with vitamin K antagonist anticoagulation, reversal of the INR to lower than 1.3, and reduction of the systolic BP to lower than 160 mmHg within 4 h is associated with reduced hematoma enlargement (29,30). Normalization of INR with four-factor prothrombin complex concentrate seems superior to fresh frozen plasma, reducing hematoma expansion (31). Idarucizumab can be used for dabigatran-associated ICH, although ICH associated with direct inhibition of thrombin or factor Xa by direct oral anticoagulants can be more complicated, requiring immediate cessation of the direct oral anticoagulants, supportive measures, and consideration of specific reversal agents (32–35).
Haemostasis: Normal Physiology, Disorders of Haemostasis and Thrombosis
Published in John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie, Basic Sciences Endocrine Surgery Rhinology, 2018
Elizabeth Jones, Russell David Keenan
Dabigatran is an oral direct thrombin inhibitor. It has a half-life of 13 hours and is mostly excreted by the kidney. There is a specific antidote available called Idarucizumab for use in an emergency setting.
Adherence to protocols for the use of reversal agents in patients treated with direct oral anticoagulants
Published in Current Medical Research and Opinion, 2023
Darko Mitrovic, Margriet van Elp, Loes Visser, Nienke van Rein, Patricia van den Bemt, Marinus van Hulst, Albert Dreijer, Heleen Lameijer, Nic Veeger, Karina Meijer, Eric van Roon
Van der Wall et al. found that inappropriate usage of idarucizumab occurred in 28% of patients; 14 of 35 patients (40%) required intervention and 11 of 53 patients (21%) presented with bleeding13. They concluded that in all the intervention cases, the procedure could have been delayed (for at least 8 h) and in eight of the bleeding complications, the situation was not considered “uncontrollable.” Dabigatran plasma levels were not measured in other patients; either they had a last intake >72 h and a normalized aPTT or they used rivaroxaban. A global study on the use of idarucizumab in clinical practice by Fanikos et al. found a low frequency of unapproved idarucizumab dosage regimens (3.3%) and minimal off-label use14. Life-threatening bleeding was the most frequent indication for idarucizumab (57.7%), followed by urgent intervention (35.9%). Among the life-threatening bleeding events, the most frequent was gastrointestinal tract bleeding (44.4%). No information was provided on whether the appropriateness of the urgent intervention was considered, while analysing the possibility of delaying the intervention or specific laboratory assays.
Treatment strategies for patients with atrial fibrillation and anticoagulant-associated intracranial hemorrhage: an overview of the pharmacotherapy
Published in Expert Opinion on Pharmacotherapy, 2020
José Miguel Rivera-Caravaca, María Asunción Esteve-Pastor, Anny Camelo-Castillo, Inmaculada Ramírez-Macías, Gregory Y. H. Lip, Vanessa Roldán, Francisco Marín
Idarucizumab is a specific monoclonal antibody antidote that specifically binds dabigatran and rapidly, safely, and dose-dependently reverses its effects without over-correction or thrombin generation. In the REVERSE-AD (Reversal of Dabigatran Anticoagulant Effect with Idarucizumab) study, idarucizumab 5 g was administered intravenously in two bolus doses of 2.5 g no more than 15 min apart to dabigatran-treated patients with anticoagulation emergencies (either ongoing severe or life-threatening hemorrhage, or emergency procedures on therapy). In this study, the primary endpoint of maximum reversal of the anticoagulant effect of dabigatran within 4 hours was 100% as assessed by dilute thrombin or Ecarin clotting time and was achieved in all patients. Based on these results, idarucizumab was approved in 2015 by the US Food and Drug Administration and the European Medicines Agency [4,22,29,98,105,116–120]. The full cohort analysis of the REVERSE-AD showed that the median time to the cessation of bleeding was 2.5 hours in patients with uncontrolled bleeding. Treatment with idarucizumab was safe with no significant adverse effects and a 6.3% and 7.4% rate of thrombotic complications (in the group with severe/life-threatening hemorrhage, and emergency procedures on therapy, respectively) [116]. However, if thrombolysis is performed after dabigatran reversal in acute ischemic stroke patients, the effectiveness and safety of the antidote could be underestimated.
Reversal agents for direct oral anticoagulants: considerations for hospital physicians and intensivists
Published in Hospital Practice, 2019
Idarucizumab, the first novel reversal agent for a DOAC (dabigatran), was approved by the US Food and Drug Administration (FDA) in 2015 for dabigatran-treated patients requiring emergency surgery or urgent procedures or with life-threatening or uncontrolled bleeding [42] and is available in most major hospitals. Idarucizumab, a humanized monoclonal antibody fragment developed specifically for dabigatran reversal [43], binds dabigatran with an affinity ~350-fold higher vs thrombin (Table 1) [44]. Being highly specific for dabigatran, idarucizumab does not bind with thrombin (despite structural similarities) or other thrombin substrates (S-2238, FV, FVIII, FXIII, fibrinogen, von Willebrand factor, protease-activated receptor 1, or protein C) and has no effect on platelet aggregation [44]. The idarucizumab-dabigatran complex is stable, with minimal dissociation of dabigatran [43]. Peak plasma concentrations of idarucizumab were achieved at the end of a 5-min infusion. A rapid decline followed, with an initial half-life of ~45 min in healthy volunteers, ensuring immediate availability in plasma for dabigatran binding [43,45].