Managing reversal of direct oral anticoagulants in emergency situations

2016 ◽  
Vol 116 (12) ◽  
pp. 1003-1010 ◽  
Author(s):  
Harry R. Büller ◽  
Anna Falanga ◽  
Werner Hacke ◽  
Jeroen Hendriks ◽  
Trudie Lobban ◽  
...  
Keyword(s):  
Task Force ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Therapeutic Benefit ◽  
Current Status ◽  
Reversal Agent ◽  
Medical Specialties ◽  
Reversal Agents ◽  
Emergency Situations

SummaryAnticoagulation is the cornerstone of prevention and treatment of venous thromboembolism (VTE) and stroke prevention in patients with atrial fibrillation (AF). However, the mechanisms by which anticoagulants confer therapeutic benefit also increase the risk of bleeding. As such, reversal strategies are critical. Until recently, the direct oral anticoagulants (DOACs) dabigatran, rivaroxaban, apixaban, and edoxaban lacked a specific reversal agent. This report is based on findings from the Anticoagulation Education Task Force, which brought together patient groups and professionals representing different medical specialties with an interest in patient safety and expertise in AF, VTE, stroke, anticoagulation, and reversal agents, to discuss the current status of anticoagulation reversal and fundamental changes in management of bleeding associated with DOACs occasioned by the approval of idarucizumab, a specific reversal agent for dabigatran, as well as recent clinical data on specific reversal agents for factor Xa inhibitors. Recommendations are given for when there is a definite need for a reversal agent (e.g. in cases of life-threatening bleeding, bleeding into a closed space or organ, persistent bleeding despite local haemostatic measures, and need for urgent interventions and/or interventions that carry a high risk for bleeding), when reversal agents may be helpful, and when a reversal agent is generally not needed. Key stakeholders who require 24–7/around-the-clock access to these agents vary among hospitals; however, from a practical perspective the emergency department is recommended as an appropriate location for these agents. Clearly, the advent of new agents requires standardised protocols for treating bleeding on an institutional level.

Reversal of oral anticoagulants

ESC CardioMed ◽  
2018 ◽  
pp. 278-281
Author(s):  
Joanne van Ryn
Keyword(s):  
Clinical Trials ◽  
Vitamin K ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Vitamin K Antagonist ◽  
Reversal Agent ◽  
Reversal Agents ◽  
Trial Testing

Oral anticoagulation reduces the risk of stroke in patients with atrial fibrillation and is effective in treating or preventing thromboembolic events. These indications have been the mainstay of vitamin K antagonist therapy for decades; however, in recent years a number of direct oral anticoagulants have also been approved for these indications. They circumvent many of the disadvantages associated with vitamin K antagonist use; however, the lack of a rapid and safe reversal strategy in emergency settings is often considered a hurdle to their more widespread use. Historically, coagulation factor concentrates have been used for rapid vitamin K antagonist reversal, though evidence from clinical trials has only been established in recent years. In addition, several new approaches to the specific reversal of anticoagulation have been developed. The first of these, idarucizumab, a specific reversal agent for dabigatran, was approved in 2015. A specific reversal agent for the factor Xa inhibitors, andexanet alfa, is currently in clinical trial testing, and a further compound, ciraparantag, is undergoing testing in healthy volunteers. This chapter discusses the mechanism of action of these reversal agents, their target anticoagulants, and the most recent data available in both volunteer and clinical trials.

A Novel Whole Blood Point-of-Care Coagulometer to Measure the Effect of Direct Oral Anticoagulants and Heparins

2018 ◽  
Vol 45 (03) ◽  
pp. 259-263 ◽  
Author(s):  
Jack Ansell ◽  
Stefan Zappe ◽  
Xuan Jiang ◽  
Lirong Chen ◽  
Solomon Steiner ◽  
...  
Keyword(s):  
High Risk ◽  
Whole Blood ◽  
Point Of Care ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Pharmacokinetic Parameters ◽  
Reversal Agents ◽  
Emergency Situations ◽  
Risk Patients

AbstractThe direct oral anticoagulants (DOACs) currently require no monitoring for routine therapy of atrial fibrillation or venous thromboembolism. Measurement of activity, however, may be important in patients with major and life-threatening bleeding, patients needing emergent surgery, in reversal situations, or in patients at high risk of bleeding or thrombosis due to underlying conditions. For these patients, a widely available and rapid turnaround assay would be optimal. To date, there is no such assay available, especially for the direct factor Xa inhibitors. This report describes the performance of a new, rapid turnaround, point-of-care (PoC) assay for measuring the activity of a range of anticoagulants, including DOACs and heparins, in emergency situations and for routine measurement in high-risk patients. Perosphere Technologies' PoC coagulometer is a handheld instrument that performs individual coagulation tests on samples of fresh whole blood (∼10 µL) with clotting activated by glass contact and endpoint determination performed by infrared spectroscopy. In preclinical studies using rats anticoagulated with therapeutic doses of edoxaban or enoxaparin, the PoC coagulometer showed a strong linear correlation between pharmacokinetic parameters and clotting time with edoxaban (r 2 = 0.994) and with enoxaparin (r 2 = 0.967). These preclinical results suggest that this PoC coagulometer would be ideal to assess the pharmacodynamic effects of anticoagulants and their reversal agents. The PoC bedside instrument delivers results within minutes and requires no more than a drop of whole blood. Studies are underway to confirm these results in humans and to further characterize the performance of the instrument.

scholarly journals Reversal Strategies for Intracranial Hemorrhage Related to Direct Oral Anticoagulant Medications

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Alok Dabi ◽  
Aristides P. Koutrouvelis
Keyword(s):  
Side Effects ◽  
Intracranial Hemorrhage ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Coagulation Cascade ◽  
Reversal Agents ◽  
United States Food ◽  
Life Threatening

Direct oral anticoagulants (DOACs) are a new class of anticoagulants that directly inhibit either thrombin or factor Xa in the coagulation cascade. They are being increasingly used instead of warfarin or other vitamin K antagonists (VKAs). Adverse side effects of DOACs may result in hemorrhagic complications, including life-threatening intracranial hemorrhage (ICH), though to a much lesser degree than VKAs. Currently there are relatively limited indications for DOACS but their usage is certain to expand with the availability of their respective specific reversal agents. Currently, only idarucizumab (antidote for dabigatran) has been United States Food and Drug Administration- (FDA-) approved, but others (andexanet-α and ciraparantag) may be approved in near future, and the development and availability of such reversal agents have the potential to dramatically change the current anticoagulant use by providing reversal of multiple oral anticoagulants. Until all the DOACs have FDA-approved reversal agents, the treatment of the dreaded side effects of bleeding is challenging. This article is an attempt to provide an overview of the management of hemorrhage, especially ICH, related to DOAC use.

scholarly journals Difficult Intraoperative Heparinization Following Andexanet Alfa Administration

2019 ◽  
Vol 3 (4) ◽  
pp. 390-394 ◽  
Author(s):  
C. James Watson ◽  
Sara Zettervall ◽  
Matthew Hall ◽  
Michael Ganetsky
Keyword(s):  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Hemodynamic Instability ◽  
The United States ◽  
Major Hemorrhage ◽  
Reversal Agents ◽  
Abdominal Aortic ◽  
United States Food ◽  
Andexanet Alfa

Direct oral anticoagulants are now commonplace, and reversal agents are recently becoming available. Andexanet alfa (AnXa), approved by the United States Food and Drug Administration in 2018, is a novel decoy molecule that reverses factor Xa inhibitors in patients with major hemorrhage. We present a case of a 70-year-old man taking rivaroxaban with hemodynamic instability from a ruptured abdominal aortic aneurysm. He received AnXa prior to endovascular surgery, and intraoperatively he could not be heparinized for graft placement. Consideration should be given to the risks and benefits of AnXa administration in patients who require anticoagulation after hemorrhage has been controlled.

scholarly journals Reversal of direct oral anticoagulants: a practical approach

Hematology ◽  
2016 ◽  
Vol 2016 (1) ◽  
pp. 612-619 ◽  
Author(s):  
Andrew W. Shih ◽  
Mark A. Crowther
Keyword(s):  
Phase 1 ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Antibody Fragment ◽  
Factor Xa ◽  
Factor Xa Inhibitors ◽  
Severe Bleeding ◽  
Thrombin Time ◽  
Ancillary Benefits ◽  
Reversal Agents

Abstract Direct oral anticoagulants (DOACs) have at least noninferior efficacy compared with other oral anticoagulants and have ancillary benefits, including overall better safety profiles, lack of the need for routine monitoring, rapid onset of action, and ease of administration. Reversal of these agents may be indicated in certain situations such as severe bleeding and for perioperative management. DOAC-associated bleeding should be risk stratified: patients with moderate or severe bleeding should have the DOAC discontinued and reversal strategies should be considered. Laboratory testing has limited utility in the acute management of bleeding; thrombin time and activated partial thromboplastin time may be useful for excluding clinically relevant levels of dabigatran. Prothrombin time is potentially useful for rivaroxaban and edoxaban, but calibrated anti-Xa assays are optimal for determining clinically relevant levels of factor Xa inhibitors. Because specific reversal agents are not widely available, supportive care and interventions for local hemostasis remain the cornerstones of therapy in the patient with DOAC-associated bleeding. Nonspecific reversal agents should be considered only in the event of severe bleeding because their efficacy is unknown, and they are associated with risk of thrombosis. Recent results from phase 3/4 studies demonstrate efficacy for an antidote to dabigatran (idarucizumab, a monoclonal antibody fragment with specificity for dabigatran) and an antidote to factor Xa inhibitors (andexanet alfa, a recombinant and inactive form of factor Xa that binds inhibitors). A universal reversal agent (ciraparantag) for many anticoagulants, including the DOACs, shows promise in results from phase 1 and 2 studies.

scholarly journals Monitoring and reversal of direct oral anticoagulants

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 117-124 ◽  
Author(s):  
Adam Cuker ◽  
Deborah Siegal
Keyword(s):  
Prothrombin Complex Concentrate ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Antibody Fragment ◽  
Factor Xa ◽  
Factor Xa Inhibitors ◽  
Severe Bleeding ◽  
Thrombin Time ◽  
Reversal Agents ◽  
Routine Monitoring

Abstract Although the direct oral anticoagulants (DOACs) do not require routine monitoring and reduce bleeding compared with warfarin, there are special circumstances in which laboratory measurement or reversal of their anticoagulant effect may be indicated. The dilute thrombin time and ecarin-based assays are able to quantify dabigatran across a broad range of concentrations, but are not widely available. A normal thrombin time excludes clinically relevant levels and a normal activated partial thromboplastin time probably excludes excess levels of dabigatran. Factor Xa inhibitors may be quantified with an anti-Xa assay calibrated with drug-specific standards. A normal prothrombin time probably excludes excess levels of rivaroxaban and edoxaban, but not apixaban. Patients with minor and moderate DOAC-associated bleeding can be treated with supportive care and general hemostatic measures. Nonspecific reversal agents (eg, prothrombin complex concentrate, activated prothrombin complex concentrate) are of unproven benefit, carry a risk of thrombosis, and should be reserved for severe bleeding. Specific reversal agents, such as idarucizumab (a monoclonal antibody fragment that binds dabigatran) and andexanet alfa (a recombinant factor Xa variant that binds factor Xa inhibitors but lacks coagulant activity), are in clinical development.

Monitoring and reversal of direct oral anticoagulants

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 117-124 ◽  
Author(s):  
Adam Cuker ◽  
Deborah Siegal
Keyword(s):  
Prothrombin Complex Concentrate ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Antibody Fragment ◽  
Factor Xa ◽  
Factor Xa Inhibitors ◽  
Severe Bleeding ◽  
Thrombin Time ◽  
Reversal Agents ◽  
Routine Monitoring

Although the direct oral anticoagulants (DOACs) do not require routine monitoring and reduce bleeding compared with warfarin, there are special circumstances in which laboratory measurement or reversal of their anticoagulant effect may be indicated. The dilute thrombin time and ecarin-based assays are able to quantify dabigatran across a broad range of concentrations, but are not widely available. A normal thrombin time excludes clinically relevant levels and a normal activated partial thromboplastin time probably excludes excess levels of dabigatran. Factor Xa inhibitors may be quantified with an anti-Xa assay calibrated with drug-specific standards. A normal prothrombin time probably excludes excess levels of rivaroxaban and edoxaban, but not apixaban. Patients with minor and moderate DOAC-associated bleeding can be treated with supportive care and general hemostatic measures. Nonspecific reversal agents (eg, prothrombin complex concentrate, activated prothrombin complex concentrate) are of unproven benefit, carry a risk of thrombosis, and should be reserved for severe bleeding. Specific reversal agents, such as idarucizumab (a monoclonal antibody fragment that binds dabigatran) and andexanet alfa (a recombinant factor Xa variant that binds factor Xa inhibitors but lacks coagulant activity), are in clinical development.

scholarly journals What we have learned about direct oral anticoagulant reversal

Hematology ◽  
2019 ◽  
Vol 2019 (1) ◽  
pp. 198-203 ◽  
Author(s):  
Deborah M. Siegal
Keyword(s):  
Oral Anticoagulant ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Management Strategies ◽  
Factor Xa ◽  
Case Fatality ◽  
Bleeding Complications ◽  
Major Health Problem ◽  
Reversal Agents ◽  
Anticoagulant Reversal

Abstract Bleeding is the main complication of oral anticoagulant (OAC) therapy, with major bleeds occurring in about 2% to 4% of OAC-treated patients per year. Although direct oral anticoagulants (DOACs) reduce the risk of major, fatal, and intracranial hemorrhage, major DOAC-related bleeding is associated with substantial morbidity and mortality, with case-fatality rates of 8% to 15% reported. Specific reversal agents for dabigatran (idarucizumab) and factor Xa inhibitors (andexanet) correct laboratory indices of anticoagulant effect. Clinical studies suggest that the majority of patients receiving these agents for DOAC-associated major bleeds experience clinical hemostasis. However, uncertainty remains regarding the incremental benefit of these agents and prothrombin complex concentrates over supportive measures alone, based on cohort studies that lacked control groups. Similar methodologic limitations preclude firm conclusions regarding the harms associated with use of these agents. Importantly, patients with DOAC-related major bleeding have substantial short-term risks of thrombosis and mortality, emphasizing the need for individualized patient assessment and protocolized bleed management strategies that include assessment of candidacy for safe resumption of OACs. With expanding indications and increasing prevalence of DOAC-eligible patients, bleeding complications and their management represent an ever-greater major health problem.

scholarly journals Direct-Acting Oral Anticoagulants and Their Reversal Agents—An Update

Medicines ◽  
2019 ◽  
Vol 6 (4) ◽  
pp. 103 ◽  
Author(s):  
Stephanie Kustos ◽  
Pius Fasinu
Keyword(s):  
Oral Anticoagulants ◽  
Anticoagulation Therapy ◽  
Factor Xa ◽  
Rapid Onset ◽  
Thrombin Inhibitor ◽  
Reversal Agent ◽  
Onset Of Action ◽  
Reversal Agents ◽  
Direct Acting ◽  
Direct Acting Oral Anticoagulants

Background: Over the last ten years, a new class of drugs, known as the direct-acting oral anticoagulants (DOACs), have emerged at the forefront of anticoagulation therapy. Like the older generation anticoagulants, DOACs require specific reversal agents in cases of life-threatening bleeding or the need for high-risk surgery. Methods: Published literature was searched, and information extracted to provide an update on DOACS and their reversal agents. Results: The DOACs include the direct thrombin inhibitor—dabigatran, and the factor Xa inhibitors—rivaroxaban, apixaban, edoxaban, and betrixaban. These DOACs all have a rapid onset of action and each has a predictable therapeutic response requiring no monitoring, unlike the older anticoagulants, such as warfarin. Two reversal agents have been approved within the last five years: idarucizumab for the reversal of dabigatran, and andexanet alfa for the reversal of rivaroxaban and apixaban. Additionally, ciraparantag, a potential “universal” reversal agent, is currently under clinical development. Conclusions: A new generation of anticoagulants, the DOACs, and their reversal agents, are gaining prominence in clinical practice, having demonstrated superior efficacy and safety profiles. They are poised to replace traditional anticoagulants including warfarin.

scholarly journals Knowledge about specific reversal agent of Greek AF patients on direct oral anticoagulants

2021 ◽  
Vol 20 (Supplement_1) ◽  
Author(s):  
A Ioannidis ◽  
A Pechlevanis ◽  
A Pechlevanis ◽  
M Paraskelidou ◽  
M Paraskelidou ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Bleeding Event ◽  
Antiplatelet Agents ◽  
City Hospital ◽  
Reversal Agent ◽  
Northern Greece ◽  
Waiting Room ◽  
Reversal Agents

Abstract Funding Acknowledgements Type of funding sources: None. Background Clinical guidelines recommend taking into account the patient’s preference when deciding on the options of direct oral anticoagulation (DOAC) therapy. Therefore, education is a prerequisite for informed, involved patients and patient-centred care. Purpose The aim of this study was to assess the patient’s awareness about the existence of the dabigatran specific reversal agent (Idarucizumab) and whether the patient was involved in the decision of the specific DOAC regimen. Methods Non-valvular atrial fibrillation (AF) patients on DOAC who visited the outpatient clinics of a city hospital in northern Greece were invited to participate. This project was part of the validation study of the Greek version of the Jessa Atrial fibrillation Knowledge Questionnaire. Analyses were performed by IBM SPSS Statistics. Results In total, there were 312 participants (168 females, 53.8%) with mean age: 64 ± 5.3 years old. The vast majority of patients (256, 82.1%) were not aware of the existence of any specific reversal agent regardless the socio-economic status (annual income, years of schooling) or the duration and type of AF. Patients that were switched from a vitamin-K antagonist (acenocoumarol) to a DOAC were more likely to be informed about specific reversal agents (31 out of 63 patients switched to DOAC, 49.2% vs. 10.0%, p < 0.05). Similarly, patients taking more than 5 pills per day were more likely to know about the reversal agent (41 of the 193 patients, 21.2% vs. 12.6%). Moreover, the majority of patients that reported any bleeding event that lead to seeking medical advice (minor or major bleeding) were informed about the specific reversal agent (35 out of 52 patients reporting bleeding event, 67.3% vs. 8.1%, p < 0.05). Inappropriately, only seven of the 38 patients (18.4%) that were also taking antiplatelet agents (mainly acetylsalicylic acid or clopidogrel) were aware of specific DOAC reversal agents. Patients with history of stoke or transient ischaemic attack were also better informed (38 out of 53 patients, 71.7% vs. 6.9%). Only about one of five patients on dabigatran (27 out of 129, 20.9%) knew about the dabigatran specific reversal agent, mainly from sources other than their doctor (e.g. journal in office waiting room). All patients agreed that they would prefer to have been informed about the current specific reversal agents when deciding on DOAC therapy. No data could be collected why patients who were informed about specific reversal agent were not prescribed dabigatran. Conclusions The sample of Greek non-valvular AF patients showed a noticeably low awareness of the existence of the specific DOAC reversal agent. It seems that DOAC prescription was a rather limited shared decision. Further research is warranted to confirm the aforementioned results.

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