per977 and Hemorrhage

Despite the improved safety-profile of direct oral anticoagulants (DOACs), bleeding complications remain an important side effect of anticoagulant treatment. Although anticoagulant-specific antidotes are available, an universal anticoagulant reversal agent in case of life-threatening bleeding or emergency surgery is not yet available. Ciraparantag, a synthetic small molecule that inactivates heparins and DOAC, is a promising new reversal agent that has been investigated in phase 2 trials. In this short review we provide an overview of the preclinical and clinical evidence of ciraparantag, and compare strengths and weaknesses of ciraparantag and the currently available anticoagulant reversal strategies.

Topics: Administration, Oral; Anticoagulant Reversal Agents; Anticoagulants; Anticoagulation Reversal; Antidotes; Arginine; Hemorrhage; Heparin; Humans; Piperazines; Recombinant Proteins

The management of life-threatening bleeding in patients who are receiving direct oral anticoagulants (DOACs) is a serious medical concern.. This review provides a concise, balanced overview of the current and future approaches for reversing the anticoagulation effects of DOACs, particularly factor Xa (FXa) inhibitors.. The anticoagulant activity of the direct thrombin inhibitor dabigatran can be reversed by idarucizumab, but until recently, options for the management of major bleeding in patients who were receiving FXa inhibitors were limited to nonspecific strategies, including supplementation of clotting factors with prothrombin complex concentrates (PCCs) or activated PCCs for attenuating anticoagulation effects. They appear as a treatment option in many hospital guidelines despite the lack of approval by the U.S. Food and Drug Administration and the lack of rigorous medical evidence supporting their use in this setting. The development of specific reversal agents may provide improved strategies for the management of bleeding. Andexanet alfa is a modified FXa molecule approved in the United States to reverse the anticoagulant effects of FXa inhibitors (rivaroxaban and apixaban) in patients with life-threatening or uncontrolled bleeding. Ciraparantag is a small-molecule inhibitor of multiple anticoagulants that has been investigated in healthy subjects.. The current guidelines for management of DOAC-associated bleeding are being updated to reflect that the reversal agent for rivaroxaban and apixaban is now available. For other FXa inhibitors, in the absence of a reversal agent, nonspecific strategies that include PCCs are recommended. The population of patients anticoagulated with DOACs is growing, and we hope that specific reversal agents will improve the approach to management of major bleeding in this population.

Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Anticoagulants; Arginine; Blood Coagulation Factors; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Humans; Piperazines; Practice Guidelines as Topic; Recombinant Proteins

The main advantage of the direct oral anticoagulants over vitamin K antagonists is reduced rates of major bleeding, especially intracranial hemorrhage. While use of different clotting factor supplements have been used in patients with direct oral anticoagulant induced major bleeding or when there is need for urgent surgery, the lack of preclinical and clinical data are concerning. Idarucizumab is a specific antibody developed with a 350-fold greater affinity for dabigatran than its pharmacologic target thrombin. Andexanet is a modified factor Xa molecule that binds the direct and indirect Xa inhibitors without being enzymatically active. Ciraparantag, has potential to reverse the anticoagulant activity of multiple agents. The pharmacology, preclinical, and clinical data that have developed these specific antidotes are reviewed in this manuscript.

Topics: Animals; Antibodies, Monoclonal, Humanized; Arginine; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Humans; Piperazines; Recombinant Proteins

The non-vitamin K antagonist oral anticoagulants (NOACs) include dabigatran, which inhibits thrombin, and apixaban, betrixaban, edoxaban, and rivaroxaban, which inhibit coagulation factor Xa. Although clinical studies of NOACs were conducted without antidotes, patient outcomes with major bleeding when receiving NOACs were no worse than those in patients treated with a vitamin K antagonist. Nonetheless, in patients with life-threatening bleeding or requiring urgent surgery, the capacity for rapid NOAC reversal is likely to increase patient safety. Three NOAC reversal agents are in various stages of development: idarucizumab, a specific reversal agent for dabigatran; andexanet alfa, which reverses factor Xa inhibitors; and ciraparantag, which is purported to reverse all NOACs. Idarucizumab is licensed in many countries, andexanet is under consideration by regulatory agencies, and ciraparantag is undergoing phase III evaluation. In the absence of licensed reversal agents for the oral factor Xa inhibitors, prothrombin complex concentrates are often used in patients taking these agents who present with life-threatening bleeding. In this Review, we summarize the approved indications for the NOACs, outline how to measure their anticoagulant effects, describe the mechanism of action of the reversal strategies, assess the preclinical and clinical data supporting their use, provide guidance on potential indications for reversal, and offer a management approach for patients treated with NOACs who present with serious bleeding or require urgent surgery.

Topics: Administration, Oral; Animals; Antibodies, Monoclonal, Humanized; Anticoagulants; Antidotes; Arginine; Blood Coagulation; Blood Loss, Surgical; Coagulants; Factor Xa; Hemorrhage; Humans; Perioperative Care; Piperazines; Postoperative Hemorrhage; Recombinant Proteins; Risk Assessment; Risk Factors; Treatment Outcome

Rivaroxaban, dabigatran, apixaban and edoxaban are the four available new oral anticoagulants (NOAC) which are currently approved for venous thromboembolism prophylaxis after total hip and knee replacement. Large phase 3 and phase 4 studies comparing NOAC with low molecular weight heparins have shown similar results regarding the efficacy and safety of these two categories of anticoagulants. Management of bleeding complications is a matter of great significance. Three reversal agents have been developed: idarucizumab, andexanet alfa and ciraparantag. Idarucizumab is now commercially available. Regarding the perioperative management of NOAC, two main scientific groups have published their own recommendations. The European Heart Rhythm Association recommends 48-h period of stoppage preoperatively for factor Xa inhibitors and at least 3 or 4 days for dabigatran, while the French Study Group on Thrombosis and Haemostasis recommends 5-day discontinuation for all NOAC. Conventional clot tests can only be used as rough indicators for laboratory assessment of the activity of NOAC. Specific laboratory tests have been developed for more accurate measurements of NOAC blood levels, including a dilute thrombin time test (Hemoclot test) and the ecarin clot test for dabigatran and chromogenic anti-factor Xa assays for direct factor Xa inhibitors. Due to the beneficial properties of NOAC, these drugs are gaining ground in daily orthopaedic practice, and many studies are being conducted in order to extend the indications of these anticoagulants agents.

Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Anticoagulants; Arginine; Blood Coagulation Tests; Dabigatran; Factor Xa; Hemorrhage; Humans; Orthopedic Procedures; Piperazines; Practice Guidelines as Topic; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Thiazoles; Venous Thromboembolism

Direct oral anticoagulants (DOAC) are indicated for stroke prevention in atrial fibrillation and for the prevention and treatment of venous thromboembolism. As any anticoagulant, they are associated with a bleeding risk. Management of DOAC-induced bleeding is challenging. Idarucizumab, antidote for dabigatran, is currently available and is part of the therapeutic strategy, whereas antidotes for anti-Xa agents are under development. Activated or non-activated prothrombin concentrates are proposed, although their efficacy to reverse DOAC is uncertain. We propose an update on DOAC-associated bleeding management, integrating the availability of idarucizumab and the critical place of DOAC concentration measurements.

Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Antidotes; Antithrombins; Arginine; Blood Coagulation Factors; Blood Transfusion; Dabigatran; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Hemostatics; Humans; Piperazines; Pyrazoles; Pyridones; Recombinant Proteins; Rivaroxaban; Stroke; Thrombophilia

Reversal agents for direct oral anticoagulants (DOACs), including factor X inhibitors and direct thrombin inhibitors, are a major concern in clinical practice. After DOACs were introduced and became widely used as an alternative for vitamin K antagonists in the management of venous thromboembolism and nonvalvular atrial fibrillation, the need for effective reversal agents has increased, particularly for life-threatening bleeding episodes related to DOACs or to reverse medication effects during urgent interventions. In the absence of specific reversal agents, prothrombin complex concentrate (PCC) and activated PCC are reasonable options to reverse bleeding associated with DOACs. However, high-quality clinical evidence is lacking. Idarucizumab is the only agent approved by the US Food and Drug Administration to reverse the effects of dabigatran; andexanet alfa and ciraparantag are also under evaluation as reversal agents for DOACs. This review summarizes the current evidence for nonspecific and specific reversal of DOACs.

Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Anticoagulants; Arginine; Blood Coagulation; Coagulants; Factor Xa; Hemorrhage; Humans; Piperazines; Recombinant Proteins; Risk Factors; Treatment Outcome

Anticoagulation therapy is indicated for management of various clinical conditions to prevent adverse events and introduction of direct oral anticoagulants (DOACs) has ushered in a new era in anticoagulation therapy. Major advantages of DOACS include fewer drug interactions and that they do not need periodic monitoring. Several patients who were not on anticoagulation before due to older age, polypharmacy/drug interaction concerns, and logistics of periodic monitoring are now on anticoagulation with DOACs. Despite their many advantages, a challenge while prescribing DOACs is very limited availability of specific reversal agents and lack of understanding or guidance about the treatment strategy in case of major life threatening bleeding or need for urgent surgery. So far only one reversal agent has been approved by the Food and Drug Administration (FDA), idarucizumab for one of the DOACs i.e., dabigatran. Several other reversal agents are under final phases of development such as andexanet alfa and PER977 (ciraparantag) and will help in developing specific strategies for reversal of these agents. In this article, we review current strategies to manage bleeding with DOACs and provide guidance to clinicians of inhibiting LF activity in vitro and in cells, as well as in animal models of anthrax infection.

Topics: Administration, Oral; Animals; Antibodies, Monoclonal, Humanized; Anticoagulants; Antifibrinolytic Agents; Arginine; Blood Coagulation; Blood Coagulation Factors; Cardiovascular Diseases; Dabigatran; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Humans; Models, Molecular; Piperazines; Recombinant Proteins

Direct oral anticoagulants (DOACs) are effective in preventing and treating venous thromboembolism, and preventing stroke in atrial fibrillation. Until recently, there has been no specific reversal agent for DOACs. Now, a specific antidote for the direct thrombin inhibitor, dabigatran has been approved for use, and antidotes for factor Xa inhibitors (rivaroxaban, apixaban and edoxaban) are being developed. We review the evidence for currently used and emerging reversal strategies, and discuss possible clinical implications, including increased prescription of DOACs, use of DOACs in clinical situations previously felt to pose too great a risk of bleeding, and use of reversal agents beyond currently approved indications.

Topics: Antibodies, Monoclonal, Humanized; Anticoagulants; Antithrombins; Arginine; Dabigatran; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Humans; Piperazines; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Thiazoles; Venous Thromboembolism

An understanding of how to counteract the anticoagulant effect of direct oral anticoagulants is essential in the event of haemorrhage, emergency surgery and overdose. This review summarizes strategies for the reversal of direct oral anticoagulants, including the use of novel agents.

Topics: Aged; Antibodies, Monoclonal, Humanized; Anticoagulants; Antidotes; Antithrombins; Arginine; Blood Coagulation Factors; Coagulants; Dabigatran; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Humans; Intracranial Hemorrhages; Male; Partial Thromboplastin Time; Piperazines; Prothrombin Time; Recombinant Proteins; Thrombin Time

Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Anticoagulants; Antidotes; Arginine; Blood Coagulation; Coagulants; Factor Xa; Hemorrhage; Humans; Piperazines; Recombinant Proteins

Novel oral anticoagulants (NOACs) are increasingly used in clinical practice, but lack of commercially available reversal agents is a major barrier for mainstream use of these therapies. Specific antidotes to NOACs are under development. Idarucizumab (aDabi-Fab, BI 655075) is a novel humanized mouse monoclonal antibody that binds dabigatran and reverses its anticoagulant effect. In a recent Phase III study (Reversal Effects of Idarucizumab on Active Dabigatran), a 5 g intravenous infusion of idarucizumab resulted in the normalization of dilute thrombin time in 98% and 93% of the two groups studied, with normalization of ecarin-clotting time in 89% and 88% patients. Two other antidotes, andexanet alfa (PRT064445) and ciraparantag (PER977) are also under development for reversal of NOACs. In this review, we discuss commonly encountered management issues with NOACs such as periprocedural management, laboratory monitoring of anticoagulation, and management of bleeding. We review currently available data regarding specific antidotes to NOACs with respect to pharmacology and clinical trials.

Topics: Administration, Oral; Animals; Antibodies, Monoclonal, Humanized; Anticoagulants; Antidotes; Arginine; Blood Coagulation; Blood Coagulation Tests; Coagulants; Drug Monitoring; Factor Xa; Hemorrhage; Humans; Piperazines; Recombinant Proteins

The properties of three oral anticoagulant-specific reversal agents are reviewed, and guidance is presented to assist pharmacists in planning for the agents' introduction to the market.. Idarucizumab, which received Food and Drug Administration approval in October 2015, is a humanized monoclonal antibody fragment that immediately neutralizes the anticoagulant effect of dabigatran, as evidenced by reduced unbound dabigatran concentrations and normalized coagulation tests. Preliminary Phase III trial results demonstrated a median maximum reversal of 100%, a median time to bleeding cessation of 11.4 hours, and normal intraoperative hemostasis in 92% of patients requiring anticoagulation reversal before an urgent procedure. Andexanet alfa is a factor Xa (FXa) decoy that binds to direct and indirect FXa inhibitors. In Phase III trials in healthy volunteers, andexanet alfa reduced anti-FXa activity by more than 90%, reduced the concentration of unbound direct FXa inhibitor, and inhibited thrombin generation. Ciraparantag is a reversal agent under development for reversal of anticoagulation with direct and indirect FXa inhibitors and certain factor IIa inhibitors; it exerts its effect through hydrogen bonding. Concerns for thromboembolic events directly related to administration of idarucizumab, andexanet alfa, or ciraparantag have not arisen. Pharmacists need to begin preparing for the introduction of these specific reversal agents through protocol development and provider education; in addition, pharmacy departments need to plan for procurement and storage. The specific reversal agents should be incorporated into antithrombotic stewardship or other clinical pharmacy programs for surveillance.. As agents that provide rapid reversal of direct oral anticoagulant activity become available, advance planning will help hospitals to optimize their use.

Topics: Antibodies, Monoclonal, Humanized; Anticoagulants; Arginine; Dabigatran; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Humans; Piperazines; Recombinant Proteins

Vitamin K antagonists are commonly used by clinicians to provide anticoagulation to patients who have or are at risk of having thrombotic events. In addition to familiarity with the dosing and monitoring of vitamin K antagonists, clinicians are accustomed to using vitamin K if there is a need to reverse the anticoagulant effect of vitamin K antagonists. There are now 4 new non-vitamin K antagonist oral anticoagulants (NOACs) that are attractive alternatives to vitamin K antagonists. Despite similar or lower rates of serious bleeding with NOACs in comparison with warfarin, there is a pressing need for strategies to manage bleeding when it does occur with NOACs and to reverse the pharmacological effect of these agents if needed. Important steps in minimizing bleeding risks with NOACs include dose adjustment of the agents in the setting of renal dysfunction and avoidance of the concomitant use of other antithrombotic agents if feasible. Laboratory measurement of the anticoagulant effect of NOACs is best accomplished with specialized assays, although some of the more widely available coagulation tests can provide information that is potentially useful to clinicians. Nonspecific hemostatic agents such as prothrombin complex concentrates and recombinant factor VIIa can be used to reverse the effect of NOACs. More specific reversing agents include the approved humanized monoclonal antibody fragment idarucizumab for reversing the effects of dabigatran, the investigational factor Xa decoy andexanet alfa, and the synthetic small molecule ciraparantag. Both andexanet and ciraparantag have been reported to reverse the effects of the anti-Xa NOACs (rivaroxaban, apixaban, and edoxaban), and a number of other anticoagulant agents in common clinical use, as well.

Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Antithrombins; Arginine; Blood Coagulation Factors; Dabigatran; Factor VIIa; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Hemostatics; Humans; Piperazines; Plasma; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Thiazoles

As expected with all antithrombotic agents, there is a risk of bleeding complications in patients receiving direct oral anticoagulants (DOACs) because of the DOAC itself, acute trauma, invasive procedures, or underlying comorbidities. For many bleeding events, a prudent course of action will be to withdraw the DOAC, then "wait and support" the patient, with the expectation that the bleeding event should resolve with time. Likewise, DOAC therapy may be interrupted ahead of a planned procedure, the stopping time being dependent on the agent involved and the patient's renal function. However, urgent reversal of anticoagulation is required in patients with serious or life-threatening bleeding or in those requiring urgent surgery or procedures. Novel specific reversal agents, either under development or recently approved, will need to be incorporated into local anticoagulation reversal protocols. For dabigatran-treated patients, idarucizumab recently has been approved for clinical use in cases of life-threatening or uncontrolled bleeding or when patients require emergency surgery or urgent procedures, both associated with a high risk of bleeding. As clinical experience with individual specific reversal agents grows, their roles in managing major bleeding events in DOAC-treated patients will become better defined. Future research, as well as ongoing use of idarucizumab, should help establish when it is appropriate to re-dose with idarucizumab, co-administer with prothrombin complex concentrates, or re-initiate DOAC after idarucizumab use. Ongoing trials should help identify the appropriate doses and expected durations of effect for andexanet alfa and ciraparantag, which are likely to vary depending on the individual oral anticoagulants.

Topics: Antibodies, Monoclonal, Humanized; Antidotes; Antithrombins; Arginine; Blood Coagulation Factors; Clinical Protocols; Dabigatran; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Hospitals; Humans; Piperazines; Practice Guidelines as Topic; Pyrazoles; Pyridones; Recombinant Proteins; Rivaroxaban

Patients taking direct oral anticoagulants (DOACs) who then need an emergency invasive procedure require specialized management strategies. Appropriate patient evaluation includes assessment of the current anticoagulation state, including timing of the last dose. DOACs require particular coagulation assays to measure anticoagulation levels accurately, although standard coagulation screening tests may provide qualitative guidance. Specialty societies have endorsed general recommendations for patient management to promote hemostasis in anticoagulated patients requiring surgery or other invasive procedures. These include general stopping rules (such as ≥24 hours for low-risk procedures and ≥48 hours for high-risk surgery with normal renal function) for elective procedures. Bridging therapy when oral anticoagulant treatment is interrupted has recently been questioned, depending on the clinical scenario. Novel agents for the reversal of DOAC-induced anticoagulation have recently been developed. Idarucizumab, a humanized monoclonal antibody fragment that selectively binds dabigatran, was recently approved for clinical use in patients with life-threatening or uncontrolled bleeding, and for patients requiring emergency interventions. Idarucizumab can streamline the pre- and periprocedural anticoagulation management of dabigatran-treated patients, as it provides fast, complete, and sustainable reversibility. Andexanet alfa is an inactive, decoy factor Xa (FXa) molecule that binds FXa inhibitors, and ciraparantag is a synthetic molecule designed to bind fractionated and unfractionated heparins, and each of the currently approved DOACs. As clinical development of the additional anti-FXa-specific anticoagulant reversal agents proceeds, the respective role of each in the management of emergency bleeding events and invasive procedures will be better defined, and it is hoped they will make important contributions to patient care.

Topics: Antibodies, Monoclonal, Humanized; Anticoagulants; Antidotes; Antithrombins; Arginine; Dabigatran; Deprescriptions; Emergencies; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; International Normalized Ratio; Piperazines; Prothrombin Time; Pyrazoles; Pyridones; Recombinant Proteins; Rivaroxaban; Surgical Procedures, Operative

Oral Factor Xa (FXa) inhibitors, a growing class of direct-acting anticoagulants, are frequently used to prevent stroke and systemic embolism in patients with atrial fibrillation and to prevent and treat venous thromboembolism. These drugs reduce the risk of clotting at the expense of increasing the risk of bleeding, and currently they have no specific reversal agent. However, andexanet alfa, a recombinant modified FXa decoy molecule, is in a late-phase clinical trial in bleeding patients, and ciraparantag, a small molecule that appears to reverse many anticoagulants including the FXa inhibitors, is in development. This review summarizes the published data to date on both drugs, which have the potential to change the management approach to patients with FXa inhibitor-associated major hemorrhage.

Topics: Animals; Antidotes; Arginine; Atrial Fibrillation; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Humans; Piperazines; Pyrazoles; Pyridones; Recombinant Proteins; Rivaroxaban; Stroke; Thromboembolism

As expected with all antithrombotic agents, there is a risk of bleeding complications in patients receiving direct oral anticoagulants (DOACs) because of the DOAC itself, acute trauma, invasive procedures, or underlying comorbidities. For many bleeding events, a prudent course of action will be to withdraw the DOAC, then "wait and support" the patient, with the expectation that the bleeding event should resolve with time. Likewise, DOAC therapy may be interrupted ahead of a planned procedure, the stopping time being dependent on the agent involved and the patient's renal function. However, urgent reversal of anticoagulation is required in patients with serious or life-threatening bleeding or in those requiring urgent surgery or procedures. Novel specific reversal agents, either under development or recently approved, will need to be incorporated into local anticoagulation reversal protocols. For dabigatran-treated patients, idarucizumab recently has been approved for clinical use in cases of life-threatening or uncontrolled bleeding or when patients require emergency surgery or urgent procedures, both associated with a high risk of bleeding. As clinical experience with individual specific reversal agents grows, their roles in managing major bleeding events in DOAC-treated patients will become better defined. Future research, as well as ongoing use of idarucizumab, should help establish when it is appropriate to re-dose with idarucizumab, coadminister with prothrombin complex concentrates, or re-initiate DOAC after idarucizumab use. Ongoing trials should help identify the appropriate doses and expected durations of effect for andexanet alfa and ciraparantag, which are likely to vary depending on the individual oral anticoagulants.

Topics: Antibodies, Monoclonal, Humanized; Anticoagulants; Arginine; Clinical Protocols; Dabigatran; Emergency Treatment; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Hospitals; Humans; Patient Selection; Piperazines; Practice Guidelines as Topic; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Surgical Procedures, Operative; Thiazoles

Patients taking direct oral anticoagulants (DOACs) who then need an emergency invasive procedure require specialized management strategies. Appropriate patient evaluation includes assessment of the current anticoagulation state, including timing of the last dose. DOACs require particular coagulation assays to measure anticoagulation levels accurately, although standard coagulation screening tests may provide qualitative guidance. Specialty societies have endorsed general recommendations for patient management to promote hemostasis in anticoagulated patients requiring surgery or other invasive procedures. These include general stopping rules (such as ≥24 hours for low-risk procedures and ≥48 hours for high-risk surgery with normal renal function) for elective procedures. Bridging therapy when oral anticoagulant treatment is interrupted has recently been questioned, depending on the clinical scenario. Novel agents for the reversal of DOAC-induced anticoagulation have recently been developed. Idarucizumab, a humanized monoclonal antibody fragment that selectively binds dabigatran, was recently approved for clinical use in patients with life-threatening or uncontrolled bleeding, and for patients requiring emergency interventions. Idarucizumab can streamline the pre- and periprocedural anticoagulation management of dabigatran-treated patients, as it provides fast, complete, and sustainable reversibility. Andexanet alfa is an inactive, decoy factor Xa (FXa) molecule that binds FXa inhibitors, and ciraparantag is a synthetic molecule designed to bind fractionated and unfractionated heparins, and each of the currently approved DOACs. As clinical development of the additional anti-FXa-specific anticoagulant reversal agents proceeds, the respective role of each in the management of emergency bleeding events and invasive procedures will be better defined, and it is hoped they will make important contributions to patient care.

Topics: Antibodies, Monoclonal, Humanized; Anticoagulants; Arginine; Blood Coagulation Tests; Emergency Treatment; Factor Xa; Hemorrhage; Humans; Perioperative Care; Piperazines; Recombinant Proteins; Withholding Treatment

Oral Factor Xa (FXa) inhibitors, a growing class of direct-acting anticoagulants, are frequently used to prevent stroke and systemic embolism in patients with atrial fibrillation and to prevent and treat venous thromboembolism. These drugs reduce the risk of clotting at the expense of increasing the risk of bleeding, and currently they have no specific reversal agent. However, andexanet alfa, a recombinant modified FXa decoy molecule, is in a late-phase clinical trial in bleeding patients, and ciraparantag, a small molecule that appears to reverse many anticoagulants including the FXa inhibitors, is in development. This review summarizes the published data to date on both drugs, which have the potential to change the management approach to patients with FXa inhibitoreassociated major hemorrhage.

Topics: Animals; Anticoagulants; Arginine; Clinical Trials as Topic; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Humans; Piperazines; Recombinant Proteins

The direct thrombin inhibitor dabigatran and the anti-Xa agents rivaroxaban, edoxaban, and apixaban are a new generation of oral anticoagulants. Their advantage over the vitamin K antagonists is the lack of the need for monitoring and dose adjustment. Their main disadvantage is currently the absence of a specific reversal agent. Dabigatran's, unlike the anti-Xa agents, absorption can be reduced by activated charcoal if administered shortly after ingestion and it can be removed from the blood with hemodialysis. Prothrombin complex concentrate, activated prothrombin complex concentrate, and recombinant factor VIIa all show some activity in reversing the anticoagulant effect of these drugs but this is based on ex vivo, animal, and volunteer studies. It is unclear, which, if any, of these drugs is the most suitable for emergency reversal. Three novel molecules (idarucizumab, andexanet, and PER977) may provide the most effective and safest way of reversal. These agents are currently in premarketing studies.

Topics: Administration, Oral; Animals; Antibodies, Monoclonal, Humanized; Anticoagulants; Antidotes; Arginine; Blood Coagulation; Coagulants; Hemorrhage; Humans; Piperazines; Risk Assessment; Risk Factors; Treatment Outcome

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.

Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Anticoagulants; Arginine; Blood Coagulation Factors; Blood Coagulation Tests; Dabigatran; Factor VIIa; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Hemostasis; Humans; Partial Thromboplastin Time; Piperazines; Prothrombin; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Thiazoles; Thrombin Time

Ciraparantag, an anticoagulant reversal agent, is a small molecule specifically designed to bind noncovalently by charge-charge interaction to unfractionated heparin and low-molecular-weight heparin. It shows binding characteristics that are similar to those of direct oral anticoagulants (DOACs). A dynamic light-scattering methodology was used to demonstrate ciraparantag's binding to the heparins and DOACs and its lack of binding to a variety of proteins including coagulation factors and commonly used drugs. Ciraparantag reaches maximum concentration within minutes after IV administration with a half-life of 12 to 19 minutes. It is primarily hydrolyzed by serum peptidases into 2 metabolites, neither of which has substantial activity. Ciraparantag and its metabolites are recovered almost entirely in the urine. In animal models of bleeding (rat tail transection and liver laceration), a single IV dose of ciraparantag given at peak concentrations of the anticoagulant, but before the bleeding injury, significantly reduced the blood loss. Ciraparantag, given after the bleeding injury, also significantly reduced blood loss. It appears to have substantial ability to reduce blood loss in animal models in which a variety of anticoagulants are used and has potential as a useful DOAC reversal agent.

Topics: Animals; Anticoagulants; Arginine; Blood Coagulation; Female; Half-Life; Hemorrhage; Humans; Male; Piperazines; Rats; Rats, Sprague-Dawley

Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Anticoagulants; Antidotes; Arginine; Consensus; Dabigatran; Evidence-Based Medicine; Factor Xa; Forecasting; Hemorrhage; Humans; Piperazines; Recombinant Proteins; Risk Factors; Thrombosis; Vitamin K

Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Anticoagulants; Arginine; Coagulants; Factor Xa; Hemorrhage; Humans; Piperazines; Recombinant Proteins; Treatment Outcome

This white paper provides a summary of presentations and discussions that were held at an Anticoagulant-Induced Bleeding and Reversal Agents Think Tank co-sponsored by the Cardiac Safety Research Consortium and the US Food and Drug Administration (FDA) at the FDA's White Oak Headquarters on April 22, 2014. Attention focused on a development pathway for reversal agents for the novel oral anticoagulants (NOACs). This is important because anticoagulation is still widely underused for stroke prevention in patients with atrial fibrillation. Undertreatment persists, although NOACs, in general, overcome some of the difficulties associated with anticoagulation provided by vitamin K antagonists. One reason for the lack of a wider uptake is the absence of NOAC reversal agents. As there are neither widely accepted academic and industry standards nor a definitive regulatory policy on the development of such reversal agents, this meeting provided a forum for leaders in the fields of cardiovascular clinical trials and cardiovascular safety to discuss the issues and develop recommendations. Attendees included representatives from pharmaceutical companies; regulatory agencies; end point adjudication specialist groups; contract research organizations; and active, academically based physicians. There was wide and solid consensus that NOACs overall offer improvements in convenience, efficacy, and safety compared with warfarin, even without reversal agents. Still, it was broadly accepted that it would be helpful to have reversal agents available for clinicians to use. Because it is not feasible to do definitive outcomes studies demonstrating a reversal agent's clinical benefits, it was felt that these agents could be approved for use in life-threatening bleeding situations if the molecules were well characterized preclinically, their pharmacodynamic and pharmacokinetic profiles were well understood, and showed no harmful adverse events in early human testing. There was also consensus that after such approval, efforts should be made to augment the available clinical information until such time as there is a body of evidence to demonstrate real-world clinical outcomes with the reversal agents. No recommendations were made for more generalized use of these agents in the setting of non-life-threatening situations. This article reflects the views of the authors and should not be construed to represent FDA's views or policies.

Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Anticoagulants; Arginine; Cardiovascular Diseases; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Humans; Piperazines; Recombinant Proteins; Stroke