Practical management of bleeding due to the anticoagulants dabigatran, rivaroxaban, and apixaban

If surgery is needed

If a patient taking a new oral anticoagulant needs to undergo elective surgery, it is important to temporarily discontinue the drug, assess the risk of bleeding, and test for renal impairment.

Renal impairment is particularly relevant in the case of dabigatran, since more than 80% of the unchanged drug is cleared by the kidneys. Decreasing the dose, prolonging the dosing interval, or both have been suggested as means to reduce the risk of bleeding in patients with renal impairment who are taking dabigatran.^32,33 Patients with normal renal function undergoing low-risk surgery should discontinue dabigatran at least 24 hours before the surgery. If the creatinine clearance is 31 to 50 mL/min, inclusively, the last dose should be at least 48 hours before the procedure for low-risk surgery, and 4 days before a procedure that poses a high risk of bleeding.^32–34 Some experts have given the same recommendations for rivaroxaban and apixaban (Table 2).³⁴

The aPTT and prothrombin time are readily available tests, but they cannot determine the residual anticoagulant effects of dabigatran, rivaroxaban, or apixaban. However, in many (but not all) cases, a normal aPTT suggests that the hemostatic function is not impaired by dabigatran, and a normal prothrombin time or an absence of anti-factor Xa activity would similarly exclude hemostatic dysfunction caused by rivaroxaban or apixaban. These tests are potentially useful as adjuncts before surgical procedures that require complete hemostasis.

Furthermore, a normal thrombin time rules out the presence of a significant amount of dabigatran. Therefore, a normal thrombin time might be particularly useful in a patient undergoing a high-risk intervention such as epidural cannulation or neurosurgery and who is normally receiving dabigatran.

Managing overdose and bleeding complications

Assessing the severity of bleeding is the key to managing bleeding complications (Table 3).

Minor bleeding such as epistaxis and ecchymosis can be managed symptomatically (eg, with nasal packing), perhaps with short-term withdrawal of the anticoagulant. Moderate bleeding such as upper or lower gastrointestinal bleeding can be managed by withdrawal of the anticoagulant, clinical monitoring, blood transfusion if needed, and treatment directed at the etiology.

Major and life-threatening bleeding (eg, intracerebral hemorrhage) requires aggressive treatment in the intensive care unit, withdrawal of the anticoagulant, mechanical compression of the bleeding site if accessible, fluid replacement and blood transfusion as appropriate, and interventional procedures. Nonspecific reversal agents might be considered in patients with major or life-threatening bleeding.

The half-life of dabigatran after multiple doses is approximately 14 to 17 hours and is not dose-dependent.⁹ Hence, if there is no active bleeding after a dabigatran overdose, stopping the drug may be sufficient. Since the pharmacodynamic effect of dabigatran declines in parallel to its plasma concentration, urgent but not emergency surgery may need to be delayed for only about 12 hours from the last dose of dabigatran.

The 2011 American College of Cardiology Foundation/American Heart Association guidelines recommend that patients with severe hemorrhage resulting from dabigatran should receive supportive therapy, including transfusion of fresh-frozen plasma, transfusion of packed red blood cells, or surgical intervention if appropriate.³⁵ However, transfusion of fresh-frozen plasma is debatable because there is no evidence to support its use in this situation. While fresh-frozen plasma may be useful in cases of coagulation factor depletion, it does not effectively reverse inhibition of coagulation factors.³⁶

Off-label use of nonspecific hemostatic agents

To date, no specific agent has been demonstrated to reverse excessive bleeding in patients taking the new oral anticoagulants. However, in view of their procoagulant capabilities, nonspecific hemostatic agents have been suggested for use in reversal of major bleeding resulting from these drugs.^37–39 Examples are:

Recombinant factor VIIa (NovoSeven) initiates thrombin generation by activating factor X.

Four-factor prothrombin complex concentrate (Beriplex, recently approved in the United States) contains relatively large amounts of four nonactive vitamin K-dependent procoagulant factors (factors II, VII, IX, and X) that stimulate thrombin formation.

Three-factor prothrombin complex concentrate (Bebulin VH and Profilnine SD) contains low amounts of nonactive factor VII relative to factors II, IX, and X. In some centers a four-factor equivalent is produced by transfusion of a three-factor product with the addition of small amounts of recombinant factor VIIa or fresh-frozen plasma to replace the missing factor VII.⁴⁰

Activated prothrombin complex concentrate (FEIBA NF) contains activated factor VII and factors II, IX, and X, mainly in nonactivated form.³⁶ Therefore, it combines the effect of both recombinant factor VIIa and four-factor prothrombin complex concentrate.³⁷

Studies of nonspecific hemostatic agents

In a study of rats infused with high doses of dabigatran, van Ryn et al³⁸ observed that activated prothrombin complex concentrate at a dose of 50 or 100 U/kg and recombinant factor VIIa at a dose of 0.1 or 0.5 mg/kg reduced the rat-tail bleeding time in a dose-dependent manner but not the blood loss, compared with controls, even with a higher dose of recombinant factor VIIa (1 mg/kg). Recombinant factor VIIa also reversed the prolonged aPTT induced by dabigatran, whereas activated prothrombin complex concentrate did not. They suggested that recombinant factor VIIa and activated prothrombin complex concentrate may be potential antidotes for dabigatran-induced severe bleeding in humans.

In an ex vivo study of healthy people who took a single dose of dabigatran 150 mg or rivaroxaban 20 mg, Marlu et al³⁷ found that activated prothrombin complex concentrate and four-factor prothrombin complex concentrate could be reasonable antidotes to these drugs.

Dabigatran-associated bleeding after cardiac surgery in humans has been successfully managed with hemodialysis and recombinant factor VIIa, although the efficacy of the latter cannot be individually assessed in the study.⁴¹

In a randomized placebo-controlled trial aimed at reversing rivaroxaban and dabigatran in healthy participants, Eerenberg et al³⁹ showed that four-factor prothrombin complex concentrate at a dose of 50 IU/kg reversed prolongation of the prothrombin time and decreased the endogenous thrombin potential in those who received rivaroxaban, but it failed to reverse the aPTT, the endogenous thrombin potential, and thrombin time in those who received dabigatran.

However, Marlu et al reported that four-factor prothrombin complex concentrate at three doses (12.5 U/kg, 25 U/kg, and 50 U/kg)—or better still, activated prothrombin complex concentrate (40–80 U/kg)—could be a useful antidote to dabigatran.³⁷

It is important to note that the healthy participants in the Eerenberg et al study³⁹ took dabigatran 150 mg twice daily and rivaroxaban 20 mg daily for 2.5 days, whereas those in the Marlu et al study³⁷ took the same dose of each medication, but only once.

The three-factor prothrombin complex concentrate products have been shown to be less effective than four-factor ones in reversing supratherapeutic INRs in patients with warfarin overdose, but whether this will be true with the new oral anticoagulants remains unknown. Furthermore, the four-factor concentrates effectively reversed warfarin-induced coagulopathy and bleeding in patients,⁴² but to our knowledge, the same is yet to be demonstrated in bleeding related to the newer agents.

Other measures

Gastric lavage or the administration of activated charcoal (or in some cases both) may reduce drug absorption if done within 2 or 3 hours of drug ingestion (Table 1). Because it is lipophilic, more than 99.9% of dabigatran etexilate was adsorbed by activated charcoal from water prepared to simulate gastric fluid in an in vitro experiment by van Ryn et al.⁴³ This has not been tested in patients, and no similar study has been done for rivaroxaban or apixaban. However, use of charcoal in cases of recent ingestion, particularly with intentional overdose of these agents, seems reasonable.

Hemodialysis may reverse the anticoagulant effects of dabigatran overdose or severe bleeding because only about 35% of dabigatran is bound to plasma proteins (Table 1). In a single-center study, 50 mg of dabigatran etexilate was given orally to six patients with end-stage renal disease before dialysis, and the mean fraction of the drug removed by the dialyzer was 62% at 2 hours and 68% at 4 hours.³² This study suggests that hemodialysis may be useful to accelerate the removal of the drug in cases of life-threatening bleeding.

Rivaroxaban and apixaban are not dialyzable: the plasma protein binding of rivaroxaban is 95% and that of apixaban is 87%.

FUTURE DIRECTIONS

Because the new oral anticoagulants, unlike warfarin, have a wide therapeutic window, routine anticoagulant monitoring is not needed and might be misleading. However, there are times when monitoring might be useful; at such times, a validated, widely available, easily understood test would be good to have—but we don’t have it—at least not yet.

Therapeutic ranges for the aPTT have been established empirically for heparin in various indications.⁴⁴ Additional study is needed to determine if an appropriate aPTT range can be determined for the new oral anticoagulants, particularly dabigatran.

Similarly, as with low-molecular-weight heparins, anti-factor Xa activity monitoring may become a more available validated means of testing for exposure to rivaroxaban and apixaban. More promising, using concepts derived from the development of the INR for warfarin monitoring,⁴⁵ Tripodi et al⁴⁶ have derived normalized INR-like assays to report rivaroxaban levels. A standardized schema for reporting results is being developed.⁴⁶ Studies are required to determine if and how this assay may be useful. Initial trials in this regard are encouraging.⁴⁷

Finally, the thrombotic risk associated with the use of nonspecific prohemostatic agents is unknown.^37,48 Additional studies are required to standardize their dosages, frequency of administration, and duration of action, as well as to quantify their complications in bleeding patients.