When treating patients in the ED who could potentially benefit from thrombolytic agents, monitoring dabigatran anticoagulation can present a challenge. There is very little information regarding the use of tissue plasminogen activator (tPA) in patients on dabigatran, with only one published case on the subject. In this case, intravenous (IV) tPA was administered just less than 4.5 hours after onset of neurologic symptoms and 7 hours after the last intake of dabigatran, with no complications and improved neurology function.14
The Interventional Management Stroke (IMS) III trial has suggested clinicians consider IV tPA in patients with acute stroke if the last dose of dabigatran was greater than 48 hours prior to presentation in the ED.15 Until further evidence becomes available, the decision to administer thrombolytics to stroke patients taking dabigatran should be made on a case-by-case basis and in consultation with a neurologist.
Noninferiority Studies
Dabigatran has been compared to enoxaparin and showed noninferiority for venous thromboembolism (VTE) prophylaxis, with a similar safety profile.16 The RE-COVER study in 2009 demonstrated the noninferiority of dabigatran compared to warfarin. In this study, patients received either the standard dose of dabigatran (150 mg orally, twice daily) or traditional dose-adjusted warfarin. In patients on the dabigatran regimen, recurrent VTE complications occurred at a rate of 2.4%, compared with the 2.1% observed in the warfarin group.17 The safety profile was also similar, with major bleeding episodes occurring in 1.6% and 1.9%, respectively.17
Another study, the RE-LY trial, also sought to prove noninferiority between dabigatran and warfarin, specifically in patients with a known history of atrial fibrillation requiring anticoagulation.18 The authors of the study concluded a clinical net benefit of dabigatran over warfarin with respect to reduction in both hemorrhagic and ischemic stroke and bleeding versus the increase of myocardial infarction.19 Further studies, however, are needed to determine the safety profile of dabigatran.
Dabigatran Reversal
Perhaps the most pressing question for the emergency physician is how to approach the bleeding patient on dabigatran. Although well-known protocols exist for the reversal of other anticoagulants such as warfarin and heparin, no clear, effective reversal agent is currently available for dabigatran. Given its relatively short half-life (12 to 24 hours), the first line of treatment should be to discontinue its use, followed by mechanical pressure or surgical hemostatic, if indicated. Transfusion of blood products (eg, packed red blood cells, fresh frozen plasma, platelets) should be administered based on the extent of the patient’s bleeding.
If these measures fail, dialysis may be considered, particularly in patients with renal insufficiency that may have bleeding secondary to dabigatran toxicity. In cases of suspected overdose, although activated charcoal is still being evaluated, Van Ryn and colleagues noted "preliminary in vitro data indicate that dabigatran etexilate can be successfully adsorbed by classical activated charcoal therapy. However, this has not been tested in vivo or in patients…additional clinically relevant models are required before this can be recommended in patients."10
Managing Dti-Associated Bleeding
Factor VII
Since recombinant activated factor VII directly activates thrombin on the surface of platelets, it is an option in cases of life-threatening DTI-associated bleeding. While laboratory data has supported this use, human studies have been less convincing, with conflicting results in two separate studies.20,21 Moreover, financial considerations may also affect the decision to use factor VII as its dollar cost is in the thousands at most institutions.22 Since the role of factor VII in life-threatening bleeding related to DTIs has yet to be defined, it is prudent to consider this option when other measures fail, understanding the variable rates of success in reversal of anticoagulation.
Prothrombin Complex Concentrates
Prothrombin complex concentrates (PCCs) have a significant place in reversing bleeding in patients on certain anticoagulants. Since these products contain all of the vitamin K-dependent clotting factors and proteins C and S, they have been used in the treatment of warfarin toxicity.
PCCs can be divided into activated and nonactivated categories. Among the nonactivated PCCs are PCC3 and PCC4. Both contain factors II, VII, IX, and X, but PCC3 products have lower concentrations of factor VII. To augment factor VII activity, it has been proposed that fresh frozen plasma or packed red blood cells be given in conjunction with a PCC3.23
Activated prothrombin complex concentrates (APCC) contain activated factor VII, along with inactivated forms of factors II, IX, X, and protein C. Animal studies appear promising for the use of PCCs in DTI-associated bleeding; however, this treatment has not yet been fully evaluated in human studies.24
A recent randomized, placebo-controlled crossover study by Eerenberg et al25 evaluated 12 healthy volunteers treated with PCC4 after receiving either dabigatran or rivaroxaban. While the PCC completely reversed anticoagulation in the rivaroxaban group, there was no reversal of anticoagulation in the dabigatran group.25 The authors made note of the study limitations, which include small sample size and the fact that healthy volunteers were used as surrogates as opposed to patients with major bleeding complications. The authors stated that "although this trial may have important clinical implications, the effect of PCC has yet to be confirmed in patients with bleeding events treated with these anticoagulants."25 This is the only human study available and serves as a starting point from which further human research can be initiated.25