Antidotes for Novel Oral Anticoagulants

Crowther, Mark

doi:10.1161/atvbaha.114.303402

Cited by 111 publications

(24 citation statements)

References 47 publications

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“…While 'antidotes' to apixaban, dabigatran and rivaroxaban exist, 16 they are parenterally delivered recombinant proteins that are not readily available outside of drug development trials. The exception is idarucizumab, which was recently approved.…”

Section: Patient Preferencementioning

confidence: 99%

Long-term prescribing of new oral anticoagulants

Chin¹,

Doogue²

2016

Aust Prescr

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SUMMARYWarfarin and the new oral anticoagulants are licensed for non-valvular atrial fibrillation and venous thromboembolism.The choice of anticoagulant depends on the characteristics of the patient and the medicine. Key considerations include patient adherence, kidney and liver function, and potential interactions with concomitant drugs. Dosing should accommodate these factors.Patients should be regularly monitored for bleeding, adherence to treatment, and changing comorbidities and concomitant drugs. Renal function should be checked at least annually.Other than idarucizumab for dabigatran, there are no widely available antidotes for the new oral anticoagulants. In a patient with normal renal and hepatic function, drug concentrations and anticoagulant effect are expected to diminish by over 90% after stopping treatment for 48 hours.

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Section: Patient Preferencementioning

confidence: 99%

Long-term prescribing of new oral anticoagulants

Chin¹,

Doogue²

2016

Aust Prescr

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“…In addition, absorption of dabigatran can be reduced by administering activated charcoal shortly after ingestion, or it can be removed from the blood via hemodialysis 36. Idarucizumab – the first clinically (US Food and Drug Administration) approved reversal agent for a NOAC – is an antibody fragment that inactivates the dabigatran molecule by binding to its thrombin-binding site and is given intravenously as a one-off dose 36,37. Other reversal agents are currently in premarketing clinical studies and claim to offer effective reversal of Factor X inhibitors (andexanet) and NOACs in general (PER977) 36,37.…”

Section: Methodsmentioning

confidence: 99%

“…Idarucizumab – the first clinically (US Food and Drug Administration) approved reversal agent for a NOAC – is an antibody fragment that inactivates the dabigatran molecule by binding to its thrombin-binding site and is given intravenously as a one-off dose 36,37. Other reversal agents are currently in premarketing clinical studies and claim to offer effective reversal of Factor X inhibitors (andexanet) and NOACs in general (PER977) 36,37. Andexanet alfa binds the Factor Xa inhibitors as well as heparin-activated antithrombin, thereby inactivating the anticoagulant.…”

Section: Methodsmentioning

confidence: 99%

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Pulmonary embolism: new treatments for an old problem

Ryan¹

2016

OAEM

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Nonvitamin K antagonist oral anticoagulants, previously referred to as novel oral anticoagulants, have emerged in recent years as attractive treatment options for acute pulmonary embolism (PE). However, despite the widespread anticipation by physicians and the approval of rivaroxaban, apixaban, dabigatran, and more recently edoxaban, there is still some reluctance to choose these newer agents over conventional treatment with heparin/vitamin K antagonists. Acute PE puts a considerable strain on emergency departments, and medical staff rely on efficient diagnosis and risk assessment to manage the condition appropriately and economically. Rivaroxaban and apixaban offer a convenient and cost-effective single-drug therapeutic approach. The ease of administration and drug management may enable earlier discharge and outpatient treatment in low-risk patients and alleviate the demands put on emergency-care infrastructures. This review discusses the current guidelines and anticoagulation options in the emergency setting for patients with acute PE and explores the reasons for the slow transition from old to new treatment options.

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“…This is important to avoid the potential risk of thrombosis inherent in reversing anticoagulation in a patient with an underlying predisposition to thrombosis. 31 In the RE-VERSE AD study, 5 of the 17 patients who did not restart anticoagulation 2 to 26 days after treatment subsequently developed a thrombotic event. 7 A similar strategy exists for the management of patients taking dabigatran who require emergency surgery or an invasive procedure (Figure 7).…”

Section: Implications For Practicementioning

confidence: 99%

Idarucizumab

et al. 2015

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F our non-vitamin K antagonist oral anticoagulants (NOACs), including the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban, apixaban, and edoxaban, are currently licensed as alternatives to heparins and vitamin K antagonists for the prevention and treatment of venous thromboembolism and for the prevention of stroke in patients with nonvalvular atrial fibrillation. Dabigatran is the only NOAC that inhibits thrombin; the others inhibit factor Xa. All of the NOACs are at least as effective as vitamin K antagonists for the prevention of stroke in patients with atrial fibrillation and for the treatment of venous thromboembolism, and they are associated with less life-threatening bleeding, in particular less intracranial hemorrhage.1,2 Nonetheless, serious bleeding can occur with NOACs. In addition, patients taking NOACs may sustain trauma and may require urgent surgery or interventions. Consequently, the availability of specific reversal agents for NOACs could improve patient management during these emergency situations.Idarucizumab is a humanized monoclonal antibody fragment that has been developed as a specific reversal agent for dabigatran. In vitro and ex vivo studies have demonstrated that idarucizumab promptly restores dabigatran-prolonged coagulation parameters to baseline values, [3][4][5] and studies in healthy volunteers and patients with life-threatening bleeding or requiring emergency surgery or invasive procedures show that it completely reverses the anticoagulant effects of dabigatran within minutes in the majority of patients. Idarucizumab was recently licensed in the United States and Europe. This article summarizes the pharmacology and clinical data on the use of idarucizumab to reverse dabigatran. Development of IdarucizumabThe first step in the development of idarucizumab was to immunize mice with dabigatran-derived haptens coupled to carrier proteins to produce antibodies against dabigatran. 3Monoclonal antibodies exhibiting the highest affinity for dabigatran were selected, and the antigen-binding fragment (Fab) was isolated (Figure 1). Murine protein sequences were replaced with human sequences, first in the constant region resulting in a chimeric Fab and then in the variable region where the amino acids were humanized through a design and screening process. The dabigatran-binding humanized Fab was then expressed in a mammalian cell line with the use of recombinant DNA technology. The use of a humanized Fab instead of an intact antibody results in a shorter half-life and a reduced potential for immunologic reactions.

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Antidotes for Novel Oral Anticoagulants

Cited by 111 publications

References 47 publications

Long-term prescribing of new oral anticoagulants

Long-term prescribing of new oral anticoagulants

Pulmonary embolism: new treatments for an old problem

Idarucizumab

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