US Pharm. 2018; 43(11)(Specialty&Oncology suppl):8-14.
ABSTRACT: The use of direct oral anticoagulants (DOACs) in the treatment and prevention of thromboembolic disorders has become increasingly prevalent. With no need for frequent blood monitoring and fewer drug and dietary interactions, DOACs present advantages over vitamin K antagonists. However, the risk of bleeding remains without adequate options for reversal. Treatment options for managing bleeding associated with DOACs include nonspecific agents such as nonactivated prothrombin complex concentrate, activated prothrombin complex concentrate, recombinant activated factor VII, fresh frozen plasma, and antifibrinolytic agents. Removal agents such as activated charcoal and hemodialysis also serve a role. The use of specific agents for removal—idarucizumab, andexanet alfa, and ciraparantag (in development)—is discussed.
Vitamin K antagonists (VKAs), such as warfarin, have been the standard of care for treating thromboembolic diseases, having a relatively safe and effective profile. However, their use is limited by their narrow therapeutic index, the need for frequent blood monitoring, and numerous food and drug interactions.1 These limitations led to the development of direct oral anticoagulants (DOACs). DOACs include the direct thrombin inhibitor Pradaxa (dabigatran) and the factor Xa inhibitors Xarelto (rivaroxaban), Eliquis (apixaban), Savaysa (edoxaban), and, most recently, Bevyxxa (betrixaban).1
DOACs offer several advantages over VKAs; however, the risk of bleeding with these drugs should not be underestimated. In randomized clinical trials, all DOACs have demonstrated a reduced risk for intracranial hemorrhage, but major and nonmajor bleeding events have varied among the agents as compared with VKAs.2 Therefore, it is imperative to fully understand how to effectively manage bleeding complications that may arise from their use.
Unlike warfarin, there are no specific anticoagulation tests available for DOACs to determine their effectiveness or to help guide practitioners in determining appropriate therapy in the instance of a bleed. However, DOACs may exhibit an effect on nonspecific anticoagulation parameters that will allow providers to better detect the degree of presence of these drugs in the bloodstream and hence guide appropriate treatment strategies for bleeding associated with them.
The preferred laboratory test and the interpretation of results vary depending on the specific type of DOAC.1 Anticoagulation tests lack standardization, and the evaluation of their results can be inconclusive.3 For example, the use of dabigatran can be detected by several tests (Table 1). The activated partial thromboplastin time (aPTT) is likely to be elevated with the use of dabigatran, but a normal result does not exclude the use of dabigatran.3 The thrombin time (TT) test should be performed when it is necessary to detect low concentrations of the drug. If the TT is normal, the presence of dabigatran can be excluded.3 Additionally, ecarin clotting test (ECT) scores also relate effectively to dabigatran plasma levels.3
For factor Xa inhibitors (Table 1), the aPTT test has little to no sensitivity.3 The prothrombin time (PT) test has some efficacy in detecting drug concentrations, although it is much more sensitive to edoxaban than others.3 The preferred anticoagulation test for factor Xa inhibitors is the anti-Xa-level test. The anti-Xa-level test does not have a standard range that correlates with a definite measure to allow for provider interpretation. The lack of availability of this test in most laboratories and delays in receiving results can decrease its utility when treating emergent patients.3 The aPTT test can be used as a functional measure of the blood's coagulation state and is beneficial in assessing the effect of anticoagulant activity when the preferred laboratory measure is unavailable.
Although DOACs lack standardization in anticoagulation testing, some tests may prove beneficial in detecting the presence of these drugs; there is generally significant variability in results that makes correlating test results to level of anticoagulation effect a challenge. Therefore, performing a thorough patient history that establishes when a DOAC was last taken, assessing possible drug interactions, and determining renal and hepatic function are often part of a practical method to assess anticoagulant activity.
Treatment Algorithm Based on Type of Bleed
The 2017 American College of Cardiology (ACC) Expert Consensus Decision Pathway provides guidance for clinicians who are managing bleeding in patients receiving DOACs.4 The key first step is to assess the severity of the bleeding by asking the following questions: 1) Is there bleeding at a critical site; 2) Is the patient hemodynamically unstable; and 3) Is there clinically overt bleeding with a hemoglobin drop of 2 g/dL or more or the need for two or more units of red blood cell transfusion? The bleeding is classified as major if it fulfills one or more of the above criteria.4 If it does not meet the above criteria for a major bleed, it is classified as a nonmajor bleed.4 Irrespective of the severity of the bleed, appropriate measures to control bleeding along with aggressive volume resuscitation using IV isotonic crystalloids should be initiated (Figure 1).4
In patients with a major bleed, the provider should determine whether or not the bleeding is at a critical site or is life-threatening. In a life-threatening or critical-site bleed, or in situations in which bleeding cannot be controlled, the pathway recommends stopping the DOAC and initiating a reversal agent.4 In patients with a nonmajor bleed, the provider should determine whether or not the bleed requires hospitalization, a procedure, or a transfusion. The pathway recommends stopping the DOAC if the bleed requires hospitalization, a procedure, or a transfusion.4 If it is determined that these are not required and hemostasis has been achieved, the pathway recommends continuing the DOAC.4 Routine reversal of DOAC therapy is not recommended for patients with a nonmajor bleed (Figure 1).4
DOAC Reversal: Nonspecific Agents
The use of nonspecific agents for reversal of bleeding caused by DOACs is a practice that has resulted from the lack of other well-established alternatives for the management of bleeding episodes. These agents do not directly bind to direct thrombin inhibitors or factor Xa inhibitors but result in reduction or reversal of bleeding through other mechanisms. Some of the agents that are used include: fresh frozen plasma (FFP), nonactivated prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (aPCC), recombinant activated factor VII, and antifibrinolytic therapy (rFVIIa).
PCC has been used as a first-line agent for factor Xa inhibitors and a second-line agent for direct thrombin inhibitors, but there are limited data to support its efficacy. In a randomized, double-blind, placebo-controlled study with a treatment dose of rivaroxaban 20 mg po twice daily and dabigatran 15 mg po twice daily, PT prolongation was completely reversed with a single dose of PCC 50 U/kg in the rivaroxaban group. However, coagulation levels of aPTT, ECT, and TT were not restored in the dabigatran group after the same PCC dose.4,5
The agent aPCC is used as a second-line therapy for reversal of DOACs because of the lack of robust evidence for its use. From a prospective study of 127 patients with spontaneous intracerebral hemorrhage (ICH), a small case series was conducted with six of these patients having DOAC-related ICH. These patients had taken rivaroxaban (n = 4), apixaban (n = 1), and dabigatran (n=1) within 48 hours of presentation. Anti-inhibitor coagulant complex (Feiba) was administered at a dose of 50 U/kg and reassessed at 3 months. The results showed that none of the patients had intracranial hemorrhage expansion or hemorrhagic or thrombotic complications.6
The use of rFVIIa to reverse the DOACs has shown possible effectiveness based on its impact on thrombin-generation tests. In an ex vivo study, 10 subjects were randomized to take a one-time dose of either rivaroxaban 20 mg or dabigatran 150 mg. Following a 2-week washout period, the alternate anticoagulant was given. Venous blood samples were taken at the time of each administration and 2 hours thereafter. Administration of rFVIIa resulted in correction of the altered lag time in both groups.5 Another study based on a mouse saphenous-vein bleeding model showed the effect of rFVIIa after dabigatran administration. The rFVIIa decreased the thrombin lag time and increased the rate and peak of thrombin without having an effect on total thrombin. It also showed that rFVIIa normalized hemostasis time at therapeutic dabigatran levels but not in supratherapeutic dabigatran levels. This cell-based model shows the possible role of rFVIIa in reversal even if its effectiveness is limited.7
FFP is not recommended for routine reversal of DOACs. Its use is primarily limited to reversal of VKAs in situations where a PCC is not available.4 The unfavorable side-effect profile of FFP, ranging from allergic reactions, potential for transmission of blood-borne infections, and circulatory overload also makes it a less desirable option.8
The role of antifibrinolytic agents in the management of bleeding related to DOAC therapy is not supported by current literature. However, because of their mechanism of action of stabilizing fibrin clots through inhibition of fibrinolysis, these agents are widely used as adjunctive therapy to prevent severe bleeding. Tranexamic acid and epsilon-aminocaproic acid have shown reduction in bleeding and transfusion requirements in the perioperative period.9 Even though there was no significant risk of thrombosis found with their use, antifibrinolytics should be used with caution in those with a prior history of thrombotic events.8
DOAC Removal Agents
Removal of a drug from the body is another way of managing DOAC-associated bleeding in specific situations where drug reversal is not possible. There are two ways of accomplishing this task, namely use of activated charcoal and hemodialysis. The use of activated charcoal has proven beneficial when used within 6 hours of ingestion of the DOAC agents. In a study with apixaban, activated charcoal 50 g reduced the mean half-life of apixaban from 13.4 hours to 5 hours when administered at 2 or 6 hours post apixaban dose.10 A case report of a patient with dabigatran overdose who received activated charcoal within 2 hours of ingestion showed favorable outcomes by inhibiting dabigatran gut absorption. Greater than 99.9% of dabigatran was neutralized by activated charcoal when taken within 2 hours. These findings suggest that activated charcoal when used within 6 hours may be efficacious in removing a drug in the case of overdose or accidental ingestion.11
Hemodialysis is a mode of drug removal that has proven efficacy only in the use of dabigatran over-exposure. Because dabigatran has relatively low plasma-protein binding, it can be removed from systemic circulation through dialysis. In an open-label study, a 4-hour hemodialysis session in seven patients with end-stage renal disease who were taking dabigatran 150 mg twice daily showed removal of the drug by 48.8% and 59.3% with 200-mL/min and 400-mL/min targeted blood flow, respectively. Less than 16% of dabigatran redistributed after the end of the hemodialysis session, which shows that hemodialysis can be used as a viable option for removal of dabigatran in emergency situations.12 However, hemodialysis is ineffective in removing the factor Xa inhibitors because they are highly protein-bound drugs. This was shown in an open-label study with edoxaban where subjects with end-stage renal disease on hemodialysis had no significant change in mean maximum plasma concentration or clearance of the drug after a hemodialysis session.13
Specific Agents for Reversal
Therapeutic agents that are specific to each class of DOACs are a relatively new development in the arsenal of reversal-agent options. These agents directly target and bind to direct thrombin inhibitors and factor Xa inhibitors and reverse their anticoagulant activity. The available options as well as the ones in development are discussed below and summarized in Table 2.
Praxbind (idarucizumab) is an FDA-approved antidote for dabigatran that has been favorably welcomed into clinical practice. Idarucizumab is a humanized fab antibody fragment that specifically binds to dabigatran with high affinity and has been approved for use in adult patients treated with dabigatran when rapid reversal is required in an emergency procedure or when life-threatening, uncontrolled bleeding is present.3 The dose used is 5 g, administered as two separate 2.5 g doses no more than 15 minutes apart.14 In the RE-VERSE AD study that included patients on dabigatran who had serious bleeding and/or required an urgent procedure, 100% of patients had reversal of bleeding as measured by ECT or diluted thrombin time (dTT) after administration of idarucizumab.14 Complete reversal was defined as a decrease in the dTT or ECT to a normal level.14 Both laboratory measurements correlate linearly with dabigatran concentrations and are used as an objective method of drug quantification.15 Median time to cessation of bleeding in those patients with serious bleeding was 2.5 hours. Thrombotic events were reported in 4.8% of patients within 30 days after treatment.14 With such findings, idarucizumab has replaced other modalities of reversal specifically for dabigatran.
Among the newer reversal agents, Andexxa (andexanet alfa) is used for targeted reversal of factor Xa inhibitors. During phase III trials, the use of andexanet alfa as a targeted reversal agent was found to be both safe and effective in patients receiving apixaban or rivaroxaban.16 The ANNEXA-A and ANNEXA-R trials evaluated andexanet alfa as an initial IV bolus followed by an infusion of up to 120 minutes.16 These trials demonstrated that after an IV bolus of andexanet alfa, the activity of antifactor Xa in those patients was significantly decreased when compared with the patients who received a placebo.16 Antifactor Xa was measured from baseline to nadir, which was defined as the smaller value of antifactor Xa at 2 to 5 minutes after the bolus or between 10 minutes before and 5 minutes after the end of the continuous infusion. The change in thrombin generation was also used as a measure of reversal activity. This was measured as the change in endogenous thrombin potential from baseline to peak after administration of andexanet or placebo.16 These trials evidenced that andexanet alfa has the ability to reverse factor Xa inhibitors by at least 80%.16 Phase IV trials are ongoing to further support the preliminary data that were used to gain FDA approval for the safe and effective use of andexanet alfa for the rapid reversal of factor Xa inhibitors.
Ciraparantag (PER977) is a small, synthetic, water-soluble new molecular entity that binds to oral direct factor Xa and direct thrombin inhibitors by charge interactions, as demonstrated by dynamic light scattering.17 In preclinical models, ciraparantag reversed the effects of the direct factor Xa inhibitors apixaban, rivaroxaban, and edoxaban without a procoagulant effect in a dose-dependent manner.17 In a phase I study, the safety, tolerability, and pharmacokinetic and pharmacodynamic effects of ciraparantag when administered alone and following a single therapeutic oral dose of edoxaban was assessed in 80 healthy volunteers. A single dose of IV ciraparantag (100-300 mg) after a dose of edoxaban fully reversed anticoagulation, measured by whole blood clotting time, within 10 minutes and sustained it for 24 hours.18 Phase II trials investigating the utility of ciraparantag for rivaroxaban and apixaban reversal are ongoing.19,20
It is clear that the management of bleeding from DOACs remains a paramount challenge with their prevalent use. Human trials are lacking to fully elucidate the efficacy and appropriate dosing of reversal agents. However, animal and human studies have provided insight in terms of effective reversal options with corresponding dosages, pharmacodynamic and pharmacokinetic profiles, and monitoring parameters. As much as these studies have illustrated available options, the current existing data leave much room for further study on the therapeutic options for reversal.
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19. Study of ciraparantag administered to volunteers anticoagulated with rivaroxaban, measure clotting times using WBCT. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03172910. Accessed August 31, 2018.
20. Phase 2 study of apixaban reversal by ciraparantag as measured by WBCT. Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT03288454. Accessed August 31, 2018.
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