per977 and edoxaban

Non-vitamin K antagonist oral anticoagulants (NOACs) include dabigatran, which inhibits thrombin, and apixaban, betrixaban, edoxaban and rivaroxaban, which inhibit factor Xa. In large clinical trials comparing the NOACs with the vitamin K antagonist (VKA) warfarin, dabigatran, apixaban, rivaroxaban and edoxaban were at least as effective for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism, but were associated with less intracranial bleeding. In addition, the NOACs are more convenient to administer than VKAs because they can be given in fixed doses without routine coagulation monitoring. Consequently, the NOACs are now replacing VKAs for these indications, and their use is increasing. Although, as a class, the NOACs have a favourable benefit-risk profile compared with VKAs, choosing among them is complicated because they have not been compared in head-to-head trials. Therefore, selection depends on the results of the individual trials, renal function, the potential for drug-drug interactions and preference for once- or twice-daily dosing. In addition, several 'special situations' were not adequately studied in the dedicated clinical trials. For these situations, knowledge of the unique pharmacological features of the various NOACs and judicious cross-trial comparison can help inform prescription choices. The purpose of this position article is therefore to help clinicians choose the right anticoagulant for the right patient at the right dose by reviewing a variety of special situations not widely studied in clinical trials.

Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Anticoagulants; Arginine; Atrial Fibrillation; Benzamides; Biomarkers; Blood Coagulation; Clinical Trials as Topic; Dabigatran; Drug Administration Schedule; Factor Xa; Heart Diseases; Humans; Piperazines; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Risk; Rivaroxaban; Stroke; Thiazoles; Thrombin; Venous Thromboembolism; Vitamin K; Warfarin

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 (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

Four non-vitamin K antagonist oral anticoagulants (dabigatran, rivaroxaban, apixaban, and edoxaban) have been approved in the United States for treatment of atrial fibrillation (AF) and venous thromboembolic disease. They have been as or more effective than the prior standards of care, with less fatal or intracranial bleeding, fewer drug and dietary interactions, and greater patient convenience. Nonetheless, the absence of the ability for clinicians to assess compliance or washout with a simple laboratory test (or to adjust dosing with a similar assessment) and the absence of an antidote to rapidly stop major hemorrhage or to enhance safety in the setting of emergent or urgent surgery/procedures have been limitations to greater non-vitamin K antagonist oral anticoagulant usage and better thromboembolic prevention. Accordingly, a Cardiac Research Safety Consortium "think tank" meeting was held in February 2015 to address these concerns. This manuscript reports on the discussions held and the conclusions reached at that meeting.

Topics: Antibodies, Monoclonal, Humanized; Antidotes; Antithrombins; Arginine; Atrial Fibrillation; Congresses as Topic; Dabigatran; Drug Monitoring; Factor Xa; Factor Xa Inhibitors; Humans; Partial Thromboplastin Time; Piperazines; Product Surveillance, Postmarketing; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Stroke; Thiazoles; Thrombin Time; Venous Thromboembolism

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, 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

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

Of the new direct oral anticoagulants, direct factor Xa inhibitors are limited by the absence of a proven reversal agent. We assessed the safety, tolerability and impact on anticoagulation reversal of ciraparantag (PER977) alone and following a 60 mg dose of the FXa inhibitor edoxaban. Escalating, single IV doses of ciraparantag were administered alone and following a 60 mg oral dose of edoxaban in a double-blind, placebo-controlled fashion to healthy subjects. Serial assessments of the pharmacokinetics and pharmacodynamic effects of ciraparantag were performed. Eighty male subjects completed the study. Following edoxaban (60 mg), a single IV dose of ciraparantag (100 to 300 mg) demonstrated full reversal of anticoagulation within 10 minutes and sustained for 24 hours. Fibrin diameter within clots was restored to normal 30 minutes after a single dose of 100 to 300 mg ciraparantag as determined by scanning electron microscopy and change in fibrin diameter quantified by automated image analysis. Potentially related adverse events were periorbital and facial flushing and cool sensation following IV injection of ciraparantag. Renal excretion of ciraparantag metabolite was the main elimination route. There was no evidence of procoagulant activity following ciraparantag as assessed by D-dimer, prothrombin fragments 1.2, and tissue factor pathway inhibitor levels. In conclusion, ciraparantag in healthy subjects is safe and well tolerated with minor, non-dose limiting adverse events. Baseline haemostasis was restored from the anticoagulated state with doses of 100 to 300 mg ciraparantag within 10-30 minutes of administration and sustained for at least 24 hours.

Topics: Administration, Oral; Adult; Arginine; Blood Coagulation; Double-Blind Method; Drug Monitoring; Factor Xa Inhibitors; Humans; Injections, Intravenous; Male; North Carolina; Piperazines; Pyridines; Thiazoles; Whole Blood Coagulation Time

Topics: Arginine; Blood Coagulation; Factor Xa Inhibitors; Heparin Antagonists; Humans; Piperazines; Pyridines; Thiazoles