American Journal of Emergency Medicine 32 (2014) 375–382

Contents lists available at ScienceDirect

American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem

Review

Practical considerations in emergency management of bleeding in the setting of target-specific oral anticoagulants☆,☆☆ Michael P. Miller, MD a, Toby C. Trujillo, PharmD b, c, d, Kristen E. Nordenholz, MD, MSc e,⁎ a

Denver Health Residency in Emergency Medicine, Denver, CO 80207 University of Colorado Skaggs, School of Pharmacy and Pharmaceutical Sciences, Aurora, CO 80045 University of Colorado, Anschutz Medical Campus Clinical Specialist-Anticoagulation/Cardiology University of Colorado Hospital, Aurora, CO 80045 d C238-V20 Pharmacy & Pharmaceutical Sciences, Aurora, CO 80045 e Department of Emergency Medicine, University of Colorado, School of Medicine, Aurora, CO 80045 b c

a r t i c l e

i n f o

Article history: Received 30 March 2013 Received in revised form 26 November 2013 Accepted 27 November 2013

a b s t r a c t The recent arrival of the target-specific oral anticoagulants (TSOACs) offers potential advantages in the field of anticoagulation. However, there are no rapid and accurate and routinely available laboratory assays to evaluate their contribution to clinical bleeding. With the expanding clinical indications for the TSOACs, and the arrival of newer reversal agents on the market, the emergency clinician will need to be familiar with drug specifics as well as methods for anticoagulation reversal. This review offers a summary of the literature and some practical strategies for the approach to the patient taking TSOACs and the management of bleeding in these cases. © 2014 Elsevier Inc. All rights reserved.

1. Background Until recently, vitamin K antagonists (VKAs) such as warfarin have been the only oral anticoagulants available for the prevention and treatment of thrombosis. The introduction of the direct thrombin inhibitor dabigatran as well as the direct factor Xa inhibitors rivaroxaban and apixaban represent potentially attractive alternatives to VKAs. These newer target-specific oral anticoagulants (TSOACs) offer several advantages over VKAs including predictable pharmacokinetics; rapid onset of action; and, in most cases, similar results for efficacy and safety. The pharmacokinetic advantages allow for fixed dosing and mitigate the need for routine laboratory monitoring or the need for anticoagulation bridging therapy in the perioperative setting. A number of recent clinical trials have led to the Food and Drug Administration (FDA) approval of dabigatran, rivaroxaban, and apixaban for stroke prevention in nonvalvular atrial fibrillation (AF) [1-6]. Rivaroxaban is also FDA approved for

☆ Disclosures: Kristen Nordenholz has participated in unrestricted research with Alere, Inc; Genentech, Inc; and Boehringer-Ingelheim. Toby Trujillo consults for Boehringer-Ingelheim, Bristol-Meyers Squibb, and Janssen Pharmaceuticals. ☆☆ Classifications: Hematology, Pharmacology, Pulmonary Embolism, Resuscitation. ⁎ Corresponding author. Department of Emergency Medicine, University of Colorado Denver, School of Medicine, Aurora, CO 80045. Tel.: +1 720 848 6777. E-mail addresses: [email protected] (M.P. Miller), [email protected] (T.C. Trujillo), [email protected] (K.E. Nordenholz). URL: http://www.ucdenver.edu/pharmacy (T.C. Trujillo). 0735-6757/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajem.2013.11.044

the prevention of venous thromboembolism (VTE) after orthopedic surgery and very recently was approved for treatment of VTE [7]. The TSOACs also have been approved for a variety of indications by various accrediting bodies around the world (Table 1). There is mounting evidence that the TSOACs can also be used for VTE prophylaxis in hospitalized medically ill patients and patients with acute coronary syndrome [8-11]. As the US population ages and research continues, it is likely that these TSOACs will be prescribed for more FDA approved as well as off-label uses. Despite the many favorable attributes of the TSOACs as compared with VKAs, they are not without their own unique clinical issues and risks. As such, it is unlikely that TSOACs will replace VKAs in all patients, and the paucity of information regarding certain clinical issues may present challenging cases. All of the TSOACs share similar hemorrhagic risk profiles in phase III clinical trials when compared with VKAs such as warfarin [12]. Each of the TSOACs have slightly different modes of hemorrhagic risk with a tendency to have lower risk of intracranial bleeding and slightly higher risks of gastrointestinal bleeding [1-6,13]. However, bleeding risk is not zero, and management of patients who bleed while on TSOACs is complicated by the fact that effective methods for both laboratory monitoring and emergent reversal of these medications remain unavailable or poorly understood. As more individuals begin taking direct oral thrombin and Xa inhibitors, it will become increasingly important for the emergency clinician to be familiar with them. Although recent reviews have addressed emerging clinical issues with the TSOACs [1418], the purpose of this review is to summarize the relevant characteristics of dabigatran, rivaroxaban, and apixaban as they apply to the

376

M.P. Miller et al. / American Journal of Emergency Medicine 32 (2014) 375–382

Table 1 Current approval of the TSOACs

Dabigatran

FDA approval

EMA approval

Stroke prevention in AF

VTE prevention after orthopedic surgery, stroke prevention in AF VTE prevention after orthopedic surgery, stroke prevention in AF, VTE treatment, management of ACS VTE prevention after orthopedic surgery, stroke prevention in AF

Rivaroxaban Stroke prevention in AF, VTE prevention after orthopedic surgery, VTE treatment Apixaban

Stroke prevention in AF

Abbreviations: EMA, European Medicines Agency; AF, nonvalvular atrial fibrillation; VTE, venous thromboembolism including deep vein thrombosis and pulmonary embolism; ACS, acute coronary syndrome.

emergency clinician, with a strong focus on practical approaches to reversal and management of bleeding. 2. Mechanism of action and pharmacokinetics Both thrombin and factor Xa are attractive targets for the inhibition of the coagulation cascade given their vital activities in promoting thrombosis as well as their location within the coagulation cascade itself. Dabigatran is a reversible inhibitor of factor IIa (thrombin) that binds directly to the active site on the thrombin molecule. Dabigatran is actually a prodrug, dabigatran etexilate that is rapidly converted to the active drug dabigatran upon oral administration. Peak plasma concentrations occur within 1 to 3 hours, and the drug has a half-life of 12 to 14 hours in patients with normal kidney function [19]. Plasma concentration has been shown to correlate directly with anticoagulant effect [20]. Unlike warfarin, dabigatran is predominately excreted unchanged by the kidneys (80%) with the remainder excreted in the bile. In patients with a creatinine clearance (CrCl) less than 30 mL/min, the half-life increases to approximately 27 hours [21]. It is critical to appreciate renal function when prescribing dabigatran. A recent case report describes a fatal gastrointestinal bleeding in a 74-year-old man with supratherapeutic dabigatran concentrations secondary to acute renal failure [22]. Dabigatran does not interact with the cytochrome P450 enzymes; however, it is a substrate for P-glycoprotein and is not devoid of potential drug-drug interactions. Consequently, emergency clinicians would be well served familiarizing themselves with potential drug-drug interac-

tions as they represent a potential source of change (either elevated or reduced) in expected plasma concentrations. Rivaroxaban is a reversible inhibitor of both free and clot bound factor Xa. Upon oral ingestion, it is rapidly absorbed with peak plasma concentrations occurring in approximately 2 to 4 hours. Like dabigatran, plasma concentration correlates directly with anticoagulant effect. The drug relies on renal elimination to a lesser degree as compared with dabigatran; one-third of the dose is eliminated, unchanged in the urine; one-third is eliminated in the urine as inactive metabolite; and the remaining one-third is eliminated in the feces [23]. Enough parent compound is cleared through the kidneys such that, with CrCl greater than 80 mL/min, the half-life of rivaroxaban is 8.3 hours, increasing to 9.5 hours in individuals with CrCl less than 30 mL/min [24]. Rivaroxaban does have significant liver metabolism, specifically through cytochrome P450 3A4, and is also a substrate of P-glycoprotein. As such, similar to the situation with dabigatran, potential drug-drug interactions must be accounted for as they may lead to significant alterations in plasma concentrations causing either bleeding or loss of efficacy. Apixaban is also a reversible inhibitor of both free and clot bound factor Xa. Peak plasma levels are achieved 1 to 3 hours after ingestion, and half-life is 10 to 14 hours in patients with normal renal function. Like dabigatran and rivaroxaban, plasma concentrations correlate directly with anticoagulant effect. Apixaban has similar characteristics to rivaroxaban in that 25% of the parent compound is cleared through the kidneys; it undergoes significant hepatic metabolism through cytochrome P450 3A4 and is a substrate of P-glycoprotein. Consistent themes for all of the available TSOACs are that reduced renal function and drug-drug interactions have the potential to alter the expected pharmacokinetic and pharmacodynamic response. In addition, because of the lack of a reliable method to assess the anticoagulant response for TSOACs such as the international normalized ratio (INR) for warfarin, drug-drug interactions for the TSOACs cannot be managed through dose adjustment and must be considered as precautions or contraindications. Table 2 compares the TSOACs and their pharmacokinetics. 3. Clinical considerations for altered pharmacokinetic/ pharmacodynamic response Although the TSOACs generally produce a much more consistent dose response as compared with oral VKAs, there are sources of potential pharmacokinetic variability, which are important to consider

Table 2 TSOAC pharmacokinetics Dabigatran

Rivaroxaban

Apixaban

Target Dosage Form Bioavailability Time to Peak Metabolism Renal excretion Substrate of P-glycoprotein? FDA-approved dosing for stroke prevention in a-fib

Factor IIa Capsule 6% 1-2 h Conjugation; no CYP involvement 80% Yes 150 mg twice daily for patients CrCl N30 mL/min 75 mg by mouth twice daily for CrCl 15-30 mL/min

Factor Xa Tablet 60%-80% 2-4 h Oxidation via CYP3A4 66% Yes 20 mg by mouth once daily for patients CrCl N50 mL/min 15 g by mouth once daily for patients with CrCl 15-50 mL/min

FDA-approved dosing for VTE prevention in hip and knee replacement FDA-approved dosing for [1] treatment of acute DVT or PE or [2] long-term prevention of recurrent DVT/PE

N/A

10 mg once daily for patients with CrCl N30 mL/min 15 mg by mouth twice daily for 21 d, then 20 mg once daily for patients with CrCl N30 mL/min 20 mg once daily for patients with CrCl N30 mL/min

Factor Xa Tablet 50%-85% 1-3 h Oxidation via CYP3A4 25% Yes 5 mg by mouth twice daily 2.5 mg by mouth twice daily for patients with ≥2 or more of the following: age N80 y, weight b60 kg, or serum creatinine N1.5 N/A

N/A

Abbreviations: CY, cytochrome; DVT, deep vein thrombosis; PE, pulmonary embolism.

N/A

M.P. Miller et al. / American Journal of Emergency Medicine 32 (2014) 375–382

when challenged with a patient who may be bleeding or clotting in the setting of TSOAC exposure. As will be discussed below, 1 drawback for the TSOACs is the lack of a readily available and reliable coagulation assay to provide quantitative information on the level of anticoagulation. As such, clinicians are required to make vital decisions with imprecise data. The presence of one of the potential factors listed in Table 3 may be helpful in recognizing whether bleeding may be due to potential overanticoagulation and whether aggressive interventions such as administration of a prohemostatic agent may be warranted. 4. Monitoring and timing of anticoagulant effect A major advance with TSOACs is the lack of a need for routine monitoring of anticoagulant effect as is the case with VKAs. However, there are a number of clinical scenarios where a precise quantitative assessment of anticoagulation would be helpful. Currently, there are no widely available, specific laboratory tests to rapidly and precisely assess the degree of real-time anticoagulation in a patient who is reportedly taking TSOACs. However, by appreciating the effects of TSOACs on common anticoagulation assays, the medical provider can gain a better understanding of whether the TSOACs are likely to be contributing to a particular patient's ability to clot. This information is critical when considering anticoagulation reversal. If a coagulation assay is used to assess the level of anticoagulation for a TSOAC, the time the assay was drawn in relation to the last oral dose must be accounted for. Unlike VKAs, the TSOACs have shorter half-lives, and plasma concentrations will follow a typical peak and trough format. Therefore, when managing a patient who is experiencing bleeding with a TSOAC, determining when the last dose was ingested by the patient is a key piece of information to help determine the best course of management. For example, if a bleeding patient's last dose of any TSOAC was 36 hours prior and there is minimal effect on any of the coagulation assays, the TSOAC is unlikely to be contributing to bleeding in any clinically significant degree. However, if the last TSOAC dose was within 1 to 2 hours, then, it is unclear to what degree the drug is contributing to bleeding or if absorption is complete. 5. The relationship of each TSOAC to familiar anticoagulation tests 5.1. Dabigatran Similar to other direct thrombin inhibitors, dabigatran has a dosedependent effect on coagulation assays such as the activated partial thromboplastin time (aPTT) as well as the prothrombin time (PT). The PT has low sensitivity to the activity of dabigatran, and therapeutic plasma concentrations of dabigatran frequently reflect none to only modest elevations in the PT, and therefore, its use is not recommended. In addition, the International Normalized Index - International Sensitivity Index method for VKAs is not suitable for application to dabigatran [25,26]. Dabigatran increases the aPTT in a curvilinear fashion. This test is rapidly available at most facilities and may be

377

useful as a qualitative assessment of dabigatran's effects but not as an accurate quantitative measure. Some clinical experts and guidelines have suggested that, in a patient who is taking dabigatran and experiences bleeding, if the aPTT is normal, then dabigatran is not likely to be present in significant amounts and contributing to the bleeding event [25]. However, a recent investigation demonstrated that depending on the aPTT reagent used, 15% to 35% of patients with a normal aPTT have plasma dabigatran concentrations greater than 100 ng/mL, well within the expected range of trough plasma concentrations on the standard 150 mg twice a day dose. As such, clinicians should use caution when interpreting aPTT results. Although a normal aPTT may rule out supratherapeutic concentrations of dabigatran, it cannot rule out with any certainty plasma concentrations in the expected range [27]. Assays that provide a better quantitative assessment of the anticoagulant effects of dabigatran include the thrombin clotting time, also known as the thrombin time (TT), as well as the ecarin clotting time (ECT). However, these assays are not universally standardized and rarely available for clinical use. The TT is very sensitive for the presence of dabigatran, and a normal result virtually excludes the presence of dabigatran. At the time of this publication, when faced with a dabigatran patient who is bleeding, the aPTT is the most readily available test; however, a normal test result cannot exclude expected plasma concentrations at standard dosing, although it does rule out supratherapeutic concentrations. A normal thrombin time does exclude the presence of any dabigatran in the plasma. Prolongations in either the aPTT or the TT simply indicate drug is present in the plasma, although precise quantification cannot be determined at this time. As previously discussed, results from coagulation testing should be interpreted within the context when the patient received their last dose of dabigatran. 5.2. Rivaroxaban Rivaroxaban plasma concentrations have a direct relationship with the PT. Importantly, the gradient of this effect varies substantially depending on the thromboplastin reagent that is used to perform the test (the reagent neoplastin is thought to be the most useful in providing linear correlation with the PT), and converting the PT values to INR values may compound this variation [28]. Depending on the thromboplastin reagent, at clinically relevant plasma concentrations, the PT is often only mildly elevated, if elevated at all [29-31]. Similarly, rivaroxaban prolongs the aPTT in a concentration-dependent manner; however, this effect is weaker than that observed on the PT. The aPTT relationship varies substantially depending on the reagent used to perform the test, and there is currently no international standardized reagent [24,32,33]. There are several other laboratory assays that have been evaluated for monitoring of rivaroxaban. Many of these techniques are not widely available. Chromogenic antifactor Xa assays [31] are now commercially available; however, the availability in the clinical

Table 3 Metabolism of the TSOACs

Renal impairment Age Hepatic impairment Drug-drug interactions

Dabigatran

Rivaroxaban

Apixaban

6-fold higher exposure when CrCl = 10-30 mL/min Age N75 y = 30% increase in trough concentrations N/A Avoid strong inhibitors a or inducers b of P-glycoprotein a

1.6-fold higher exposure when CrCl = 15-29

1.44-fold higher exposure when CrCl = 15-29

Mean AUC 1.5-fold higher in age N65 y

Mean AUC 1.3-fold higher in age N65 y

2.3-fold increase exposure in Child-Pugh B Avoid strong inhibitors a of P-glycoprotein and CYP 3A4

N/A Avoid strong inhibitorsa of P-glycoprotein and CYP 3A4

Abbreviations AUC, area under the curve. a Strong inhibitors of P-glycoprotein and CYP 3A4 are amiodarone, diltiazem, verapamil, quinidine, felodipine, erythromycin, and azithromycin. b Strong P-glycoprotein inducers are carbamazepine, phenytoin, rifampin, and St John's wort.

378

M.P. Miller et al. / American Journal of Emergency Medicine 32 (2014) 375–382

setting at this time is not consistent. Thromboelastography has shown a concentration-dependent prolongation of R and K. The Heptest as well as the prothrombinase-induced clotting time have also shown potential utility in monitoring the effects of rivaroxaban. None of these assays are routinely available or clearly superior to the PT for this purpose at this time [24,32,33]. At the time of this publication, when faced with a rivaroxaban patient who is bleeding, the PT is still the most available and useful assay to use; a prolonged PT simply represents that some drug is still present. Assays that can precisely assess the anti-Xa activity and return results correlated to plasma concentrations of rivaroxaban will likely become more readily available in the near future. If such an assay is available it would be preferable to the PT in an emergent setting in evaluating the anticoagulant activity from rivaroxaban [31].

activated PCC (aPCC). It contains clinically significant quantities of factors II, VII, IX, and X, with the factor VII component coming in the activated form. Because these products are activated, there is the very real question of safety regarding thrombotic risk and swinging the pendulum to the other side of hemostasis. Ehrlich et al [34] have reported a low incidence of thrombotic adverse events of 4 per 100 000 FEIBA infusions and a dose-dependent effect on the incidence of thrombosis in hemophiliacs [34]. In a meta-analysis by Hsia et al [35], arterial but not venous thrombosis was reported, but overall mortality was not increased especially using therapeutic doses. However, dosing in the setting of the TSOACs is not defined. Given that patients who are taking TSOACs are at high risk for thrombotic events, the risk of adverse effects may be higher than in patients who are not prescribed anticoagulants. To avoid overreversal, minimum doses of reversal agents must be clarified.

5.3. Apixaban 7. Dabigatran Less information is available for apixaban and its effect on a variety of coagulation assays. As a direct Xa inhibitor, apixaban's effect on various laboratory assays is similar to those of rivaroxaban. Prothrombin time is likely the most sensitive and widely available test to detect apixaban activity in plasma, but this test is limited by the high variability between different reagents, a variability that is exacerbated by conversion to the INR [24,33]. Chromogenic antifactor Xa assays appear to be useful as well, but again, the availability of these in the clinical environment is limited. As with rivaroxaban, when faced with a bleeding patient on apixaban, the PT is the most useful assay, provided a chromogenic Xa assay is not available and providing only qualitative information on the presence of the drug. 6. Management of bleeding in patients presumed to be on a TSOAC 6.1. Resuscitation When managing severe or life-threatening bleeding in the setting of potential TSOACs, it is important to prioritize basic principles of resuscitation and hemorrhage control. These methods include direct pressure, elevation, transfusion of fluids, and blood products as well as surgical intervention. In the absence of widely available and highly specific laboratory parameters for detecting active anticoagulation, one must consider time of last TSOAC ingestion as well as the patient's renal function, specifically CrCl, when determining how likely the drug is to be contributing to the hemorrhage. Furthermore, in the setting of acute overdose, hemodialysis and administration of activated charcoal may be appropriate. 6.2. Reversal After resuscitation and supportive care, there are 2 basic strategies for management of bleeding in the presence of anticoagulation: factor replacement and prohemostatic agents. 6.2.1. Factor replacement Factor replacement includes administration of fresh frozen plasma (FFP) and the prothrombin complex concentrates (PCCs). In the case of VKAs such as warfarin, the administration of vitamin K allows the vitamin K–dependent factors to be regenerated. However, vitamin K has no role in the reversal of the TSOACs. 6.2.2. Prohemostatic agents The second overall strategy of management of emergent bleeding consists of adding prohemostatic agents, which are activated products such as factor VIIa and FEIBA (Baxter Healthcare Corporation, Vienna, Austria). Recombinant factor VIIa (rFVIIa) is an activated factor and has procoagulant properties because it can generate thrombin even in the absence of tissue factor. FEIBA is the only commercially available

There are several potential methods for dabigatran reversal. 7.1. Factor replacement 7.1.1. Fresh frozen plasma Fresh frozen plasma, which can be obtained from the blood bank after a thawing period, contains all clotting factors, including some thrombin. Although FFP may be indicated in the resuscitation of an acutely bleeding patient, it remains unclear whether it is effective in reversal of anticoagulation with dabigatran in humans because dabigatran works by inhibition of and not depletion of factors [36]. Studies suggest that FFP is not as effective as PCC in achieving reversal. Table 4 details the reversal of the TSOACs using different therapies. 7.1.2. Prothrombin complex concentrates Prothrombin complex concentrates come in 3-factor (II, IX, X) as well as 4-factor (II, VII, IX, X) varieties. Until recently, only 3-factor PCC was available in the United States. Currently, the FDA has approved a 4-factor PCC (K Centra, CSL -Behring LLC, Kankakee, IL) [37] for the management of warfarin-related bleeding [38]. Activated 4-factor PCCs, meaning that factor VII specifically is activated (Feiba VH) [39], is also available, but this is a prohemostatic agent and will be discussed below. These medications, which may be located in the pharmacy or the blood bank, depending on institutional preference are concentrated, making them a potentially attractive alternative to FFP when large volume infusion is not desired. Furthermore, they have an immediate onset of action. There are limited data available on the effectiveness of PCCs in reversing dabigatran. In an unpublished study by van Ryn et al, rats were given dabigatran in supratherapeutic doses, which increased coagulation parameters. Subsequent administration of 4-factor PCCs (Beriplex, CSL -Behring LLC; Kankakee, IL and Octaplex, OctaPharma, Toronto, Ontario, Canada) decreased the bleeding time but did not change the aPTT, ECT, or TT. Prothrombin time was also reversed, but its reversal did not correlate with reversal of bleeding time [40]. The results of van Ryn et al suggest that although 4-factor PCCs and aPCCs may reverse the effects of dabigatran, this reversal may not be detected by currently available coagulation parameters. Importantly, bleeding time is not prolonged at therapeutic doses of dabigatran in humans, further clouding these results. Pragst et al [41] demonstrated that the 4-factor PCC Beriplex significantly improved blood loss and time to hemostasis in the rabbit model in a relationship that was dose dependent. In the mouse model of intracranial hemorrhage of Zhou et al [42], a 4-factor PCC was shown to prevent hematoma expansion after low-dose (4.5 mg/kg) as well as high-dose (9 mg/kg) dabigatran administration. In the only randomized, placebo-controlled study on human subjects, Eerenberg et al [43] studied the effects of a 4-factor PCC

M.P. Miller et al. / American Journal of Emergency Medicine 32 (2014) 375–382

379

Table 4 Data for potential agents for reversal of the TSOACs Reversal agent

Dabigatran

Rivaroxaban

FFP

Mouse model [42]: 200 μL reduced volume of ICH for high-dose (9 mg/kg) but not low-dose (4.5 mg/kg) dabigatran. No change in mortality No data Rabbit model [41]: (Beriplex 20, 35, or 50 IU/kg) decreased blood loss and time to hemostasis in dose-dependent manner Mouse model [42]: (Beriplex 100 U/kg) prevented excess ICH expansion and decreased bleeding time; both dose dependent (Beriplex 50 U/kg) prevented excess ICH expansion (no change in bleeding time) (Beriplex 25 U/kg) prevented excess ICH expansion (no change in bleeding time) Rat model [40]: (Beriplex or Octaplex) decreased bleeding time but did not change the aPTT, ECT, or TT. PT reversed, but its reversal did not correlate with reversal of bleeding time. Human healthy volunteers [43]: (Cofact 50 IU/kg) Lab only: No change in aPTT, TT, or ECT. No clinical bleeding assessment was done. Human healthy volunteers [45] (Kanokad; 12.5, 25, and 50 U/kg) Lab only: concentration-dependent increase in ETP-AUC; lowest dose reversed back to baseline. No clinical bleeding assessment was done. Mouse model [42] rVIIa (8 mg/kg) did not prevent intracranial hematoma expansion in high- or low-dose dabigatran. Rat model [40] (rFVIIa) decreased bleeding time but did not change the aPTT, ECT, or TT. PT reversed, but its reversal did not correlate with reversal of bleeding time. Human healthy volunteers [45] (rFVIIa, Novoseven tested at 20, 60, and 120 μg/kg). Highest dose decreased the thrombin lag time. No clinical bleeding assessment was done. Rat model [40] (FEIBA VH) decreased bleeding time but did not change the aPTT, ECT, or TT PT reversed, but its reversal did not correlate with reversal of bleeding time. Human healthy volunteers [45]: (FEIBA 20, 40, 80, and 160 U/kg), concentration-dependent increase in ETP-AUC; lowest dose reversed back to baseline. No clinical bleeding assessment was done. Human patients ex vivo [46]: (FEIBA 0, 25, 50, 100 IU/kg). Improved abnormal thrombin generation parameters. No clinical measurements.

No data

3-factor PCC Nonactivated 4-factor PCC

rFVIIa

FEIBA

No data Rabbit model [51]: (Kaskadil; LFB, Les Ullis, France; 40 U/kg) decreased aPTT time and TEG clotting time but did not decrease blood loss Human healthy volunteers [43] (Cofact 50 IU/kg) Lab only: PT immediately reversed. No clinical bleeding assessment was done Human healthy volunteers [45]: (Kanokad; 12.5, 25 and 50 U/kg) Lab only: Lower doses reversed the ETP-AUC to near baseline. Higher doses overcorrected and could be harmful. No clinical bleeding assessment was done.

Rabbit model [51]: (150 μg/kg) decreased bleeding time but did not decrease blood loss Human healthy volunteers [45] (rFVIIa, Novoseven tested at 20, 60, and 120 μg/kg) completely reversed the thrombin lag time to near baseline value and decreased time to peak thrombin concentration. No clinical bleeding assessment was done

Human healthy volunteers [45] (FEIBA 20, 40, 80, and 160 U/kg), decreased time to peak thrombin concentration. Lowest dose reversed ETP-AUC to near baseline while higher doses overcorrected. No clinical bleeding assessment was done

Abbreviations: ICH, intracerebral hemorrhage; TEG, thrombelastographic; ETP-AUC, endogenous thrombin potential–area under curve.

(Cofact, Sanquin, Amsterdam, The Netherlands) on various coagulation parameters in individuals who were taking 150 mg of dabigatran twice per day. They found that dabigatran increased the aPTT, ECT, and TT but that Cofact did not significantly change these laboratory values. However, Bernstein et al [44] suggest that these results should be interpreted with caution based on the concentration of the factors in this preparation of non-aPCC, the single dose used and the lack of clinical correlation between coagulation markers and hemostasis.

and especially FEIBA seemed to be sufficient to reverse dabigatran. Similarly, Khoo et al [46] showed that FEIBA improved abnormal thrombin generations parameters after ex vivo adding FEIBA to blood of 8 patients taking dabigatran. The 50 IU/kg FEIBA dose was effective at improving thrombin generation leading the authors to recommend that even lower doses of FEIBA be explored [46].

7.2. Prohemostatic agents

7.3.1. Charcoal There are limited data on the use of oral activated charcoal in the setting of dabigatran ingestion, but an in vitro study by van Ryn et al [47] suggests that it may be beneficial in the setting of acute overdose. The researchers dissolved dabigatran in acidic water (mimicking gastric pH) and subsequently applied activated charcoal; greater than 99.9% of the drug was adsorbed.

7.2.1. Recombinant activated factor VII or FEIBA Similar to the PCCs, rFVIIa reduced bleeding time in the van Ryn rat-tail model and normalized the PT but had no effect on the aPTT, TT, or ECT [40]. In the mouse model of Zhou et al [42], rFVIIa did not prevent intracranial hematoma expansion in mice on high-dose or low-dose dabigatran. In a more recent cross-over study by Marlu et al [45], 10 healthy volunteers with no family history for bleeding or thrombosis and no renal or liver failure took a single tablet of either dabigatran (150 mg) or rivaroxaban (20 mg) followed by a 2-week washout period before switching to the other agent. Thrombin generation times were tested immediately before and 2 hours after each ingestion. Subjects with varying doses of 3 reversal agents: rFVIIa (Novoseven; NovoNordisk, Copenhagen, Denmark), tested at 120 μg/kg [8], and at 0.5 and 1.5 μg/ mL final concentration; aPCC (FEIBA), tested at final concentrations of 0.25, 0.5, 1 (corresponding to 80 U/kg) and 2 U/mL; and the nonactivated 4-factor PCC (Kanokad; LFB, Courtaboeuf, France) tested at the final concentration of 0.25, 0.5 (corresponding to 25 U/kg), and 1 U/mL. Only rFVIIa and FEIBA corrected the dabigatran-induced lag time of thrombin generation. Although this was a small study on healthy controls and there were no clinical end points, the importance of dosing was paramount, and they concluded that lower doses of PCC

7.3. Other management strategies

7.3.2. Hemodialysis Dabigatran has relatively low plasma protein binding (35%), making it an attractive candidate for removal by hemodialysis [48]. In a study of 6 volunteers undergoing hemodialysis for end-stage renal disease, 62% of the drug was removed after 2 hours, and 68% was removed after 4 hours [25]. Consideration of this therapy must take into account the practicality of obtaining appropriate vascular access for dialysis in an individual who is anticoagulated. 8. Rivaroxaban and apixaban 8.1. Fresh frozen plasma We were unable to find any data or scientific rationale regarding the use of FFP to reverse anticoagulation with rivaroxaban or apixaban.

8.3. Recombinant factor VIIa There are limited and conflicting data available regarding the use of rFVIIa to reverse the Xa inhibitors rivaroxaban and apixaban. A recent rabbit model demonstrated that 150 μg/kg of rFVIIa improved aPTT as well as several thromboelastographic parameters but did not reduce bleeding in rabbits on rivaroxaban [51]. A baboon model of rivaroxaban demonstrated that 210 μg/kg of rFVIIa significantly reduced bleeding time to 5 minutes, but this effect was lost at 30 minutes from time of drug administration [52]. The study of Marlu et al [45] described above investigated PCC, rFVIIa, and FEIBA. Recombinant factor VIIa even in the lowest concentration did reverse the rivaroxaban-induced prolonged thrombin lag time, although this was a laboratory result and may not be correlated with hemostasis. We were unable to find any data dealing directly with the use of rFVIIa for reversal of apixaban.

1. Consider activated charcoal if within 2-3 h of an overdose 2. Consider 4-PCC (25-50 IU/kg) over aPCC (Feiba VH 20-40 U/kg)a 3. Or factor VIIa (20 U/kg) may repeat every 2 h

Apixaban

1. Check apixaban calibrated anti-Xa level if available: if normal, suggests drug contributing minimally to clinical scenario. 2. PT: Unlikely to be helpful for apixaban, most assays and reagents minimally sensitive to drug. 3. Consider time since last dose of drug 4. Check CrCl

Rivaroxaban

In the previously mentioned study by Eerenberg et al [43], 12 healthy male volunteers who had taken 20 mg of rivaroxaban twice daily for 5 days were subsequently treated with 50 U/kg of a 4-factor non-aPCC (Cofact), and their coagulation parameters were monitored. Their PT values and endogenous thrombin potential (ETP) normalized immediately, and the authors concluded that “a non-activated PCC immediately reverses the effect of full-dose rivaroxaban in healthy individuals.” However, it is unclear if this change in laboratory parameters would reflect a concurrent change in bleeding. Marlu et al [49] suggested further caution in interpreting these results because the PT must be interpreted with respect to the specific thromboplastin agent used. A clinically based efficacy analysis is needed. A separate study evaluated the effects of 50 U/kg of the 4-factor PCC Beriplex on rats who had received high-dose rivaroxaban (2 mg/kg). Bleeding time nearly normalized after administration of the PCC, and PT was also reduced [50]. These authors were not able to find data addressing the use of PCCs to reverse apixaban specifically.

1. Check rivaroxaban calibrated anti-Xa level if available: if normal, suggests drug contributing minimally to clinical scenario 2. PT: (if high sensitivity reagent used), if PT normal, suggests drug contributing minimally to clinical scenario. If low-sensitivity reagent used, PT is not reliable 3. Consider time since last dose of drug 4. Check CrCl Same as dabigatran

8.2. Prothrombin complex concentrates (nonactivated)

1. Consider activated charcoal if within 2-3 h of an overdose 2. Consider 4-PCC (25-50 IU/kg) over aPCC (Feiba VH 20-40 U/kg) 3. Or factor VIIa (20 U/kg) may repeat every 2 h

M.P. Miller et al. / American Journal of Emergency Medicine 32 (2014) 375–382

Same as dabigatran

380

4-PCC, K-Centra (available in the United States), Beriplex, or Octaplex. a

Severe bleeding (supportive care and resuscitation measures have been started)

1. Control bleeding 2. Check CrCl 3. Consider withholding further anticoagulation 1. Consider activated charcoal if within 2-3 h of an overdose 2. Dialysis 3. Consider aPCC (Feiba VH 20-40 U/kg) 4. Or 4-PCC (25-50 IU/kg) a 5. Or factor VIIa (20 U/kg) may repeat every 2 h Minor bleeding

The advent of the TSOACs offers potential clinical advantages for anticoagulation therapy, but there are still many unanswered questions. First optimal serum measurement strategies have not been developed for routine clinical use, and there are no specific tests available to reliably test the contribution of each TSOAC to emergency bleeding. The definitive approach to severe bleeding in the presence of TSOACs is still not clear. Clinical trials are needed. Currently, emergency clinicians must base their management decisions on in vitro animal models and laboratory evaluations in healthy human controls. Therefore, basic strategies for assessing patients on TSOACs and managing hemorrhage apply (Table 5). Furthermore, specific therapeutic agents may not be available at all facilities. It is critical that emergency departments and critical care environments anticipate these needs and prepare hospital-specific protocols or guidelines to assist the clinician.

Dabigatran

9. Discussion

Table 5 Laboratory evaluation and management of acute bleeding

8.4.2. Hemodialysis We were unable to find any data regarding the use of hemodialysis or plasma exchange in the setting of rivaroxaban or apixaban use.

1. Check TT: if normal, suggests drug contributing minimally to clinical scenario 2. aPTT only reliably excludes supra-therapeutic drug levels 3. Consider time since last dose of drug 4. Check CrCl

8.4.1. Charcoal The FDA advisory committee reports a rat model showing a 65% decrease in the area under the concentration curve when charcoal was administered 15 minutes after rivaroxaban ingestion [53].

Laboratory assessment to determine if drug is contributing to bleeding

8.4. Other management strategies

M.P. Miller et al. / American Journal of Emergency Medicine 32 (2014) 375–382

The authors could not find data to support desmopressin and fibrinolytic therapies of tranexamic acid and aminocaproic acid in the specific setting of TSOAC-associated bleeding; however, these may be considered in severe bleeding from trauma [54]. Local tranexamic acid has been described in the setting of controlling dental bleeding in patients continued on warfarin anticoagulation during dental extractions [55]. This approach might be considered in the future for localized bleeding in other anticoagulated patients. 9.1. Future directions Advancements in the management of bleeding in patients taking TSOACs will depend on individual advancements in the ability to quantitatively assess the level of anticoagulation with the TSOACs as well as the development and market of specific antidotes for each agent. With respect of coagulation monitoring, it was previously mentioned that chromogenic Xa assays will become standardized and more widely available for the direct factor Xa inhibitors such as rivaroxaban and apixaban. A Hemoclot direct thrombin inhibitor assay (HYPHEN BioMed, Neuville Sur Oise, France) is licensed and approved in Europe and Canada, which provides a reproducible measure of dabigatran anticoagulant activity [56]. Development of an antidote for dabigatran involves a recombinant monoclonal antibody targeted against dabigatran, which may reverse the anticoagulative effect [57]. With respect to the Xa inhibitors, a “dummy” Xa molecule has been developed and is in testing as a potential antidote that would work for any Xa inhibitor, including the synthetic injectable Xa inhibitor fondaparinux [58]. 10. Conclusion With the recent arrival of and expanding indications for the novel oral anticoagulants, the emergency physician will need to be familiar with drug specifics as well as methods for anticoagulation reversal. This article offers a summary of the literature and some practical strategies for the approach to the patient taking TSOACs. References [1] Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361(12):1139–51. [2] Pradaxa (dabigatran) [Package Insert]. Ridgefield, CT, USA: Boehringer-Ingelheim Pharmaceuticals Inc.; Prescribing Information; 2013. [3] Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365(10):883–91. [4] Xarelto (rivaroxaban) [Package Insert]. Titusville, NJ, USA: Janssen Pharmaceuticals Inc. Prescribing Information; 2013. [5] Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365(11):981–92. [6] Eliquis (apixaban) [Package Insert]. Middlesex, UK: Bristol Myers Squibb/Pfizer Inc. Prescribing Information; 2013. [7] Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363(26):2499–510. [8] Goldhaber SZ, Leizorovicz A, Kakkar AK, et al. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med 2011;365(23): 2167–77. [9] Alexander JH, Lopes RD, James S, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011;365(8):699–708. [10] Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012;366(1):9–19. [11] Oldgren J, Wallentin L, Alexander JH, et al. New oral anticoagulants in addition to single or dual antiplatelet therapy after an acute coronary syndrome: a systematic review and meta-analysis. Eur Heart J 2013;34(22):1670–80. [12] Weitz JI, Eikelboom JW, Samama MM, et al. New antithrombotic drugs: antithrombotic therapy and prevention of thrombosis: American College of Chest Physicians evidence-based clinical practice guidelines (9th edition). Chest 2012;141(2 Suppl):e120S–51S. [13] Miller CS, Grandi SM, Shimony A, et al. Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Am J Cardiol 2012;110(3):453–60. [14] Siegal DM, Crowther MA. Acute management of bleeding in patients on novel oral anticoagulants. European heart journal 2013;34(7):489–98.

381

[15] Pollack CV. Managing bleeding in anticoagulated patients in the emergency care setting. J Emerg Med 2013;45(3):467–77 doi:10.1016/j.jemermed.2013.03.016. [Epub 2013 Jun 18]. [16] Pollack CV. New oral anticoagulants in the ED setting: a review. Am J Emerg Med 2012;30(9):2046–54 doi: 10.1016/j.ajem.2012.04.005. [Epub 2012 Jul 12]. [17] Peacock WF, Gearhart MM, Mills RM. Emergency management of bleeding associated with old and new oral anticoagulants. Clin Cardiol 2012 Dec;35(12): 730–7. http://dx.doi.org/10.1002/clc.22037. [Epub 2012 Jul 18]. [18] Brem E, Koyfman A, Foran M. Review of recently approved alternatives to anticoagulation with warfarin for emergency clinicians. J Emerg Med 2013;45(1): 143–9 doi: 10.1016/j.jemermed.2012.11.032. [Epub 2013 Jan 30]. [19] Blech S, Ebner T, Ludwig-Schwellinger E, et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008;36(2):386–99. [20] Liesenfeld KH, Schafer HG, Troconiz IF, et al. Effects of the direct thrombin inhibitor dabigatran on ex vivo coagulation time in orthopaedic surgery patients: a population model analysis. Br J Clin Pharmacol 2006;62(5):527–37. [21] Stangier J, Rathgen K, Stahle H, et al. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an openlabel, parallel-group, single-centre study. Clin Pharmacokinet 2010;49(4): 259–68. [22] Maddry JK, Amir MK, Sessions D, et al. Fatal dabigatran toxicity secondary to acute renal failure. Am J Emerg Med 2013;31(2):462.e1–2. [23] Kubitza D, Becka M, Mueck W, et al. Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct factor Xa inhibitor. Br J Clin Pharmacol 2010;70(5):703–12. [24] Barrett YC, Wang Z, Frost C, et al. Clinical laboratory measurement of direct factor Xa inhibitors: anti-Xa assay is preferable to prothrombin time assay. Thromb Haemost 2010;104(6):1263–71. [25] Stangier J, Rathgen K, Stahle H, et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. British journal of clinical pharmacology 2007;64(3): 292–303. [26] Van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010;103(6):1116–27. [27] Hawes EM, Deal AM, Funk-Adcock, et al. Performance of coagulation tests in patients on therapeutic doses of dabigatran: a cross-sectional pharmacodynamic study based on peak and trough plasma levels. J Thromb Haemost 2013;11: 1493–502. [28] Harenberg J, Erdle S, Marx S, et al. Determination of rivaroxaban in human plasma samples. Semin Thromb Hemost 2012;38(2):178–84. [29] Mueck W, Eriksson BI, Bauer KA, Borris L, Dahl OE, Fisher WD, et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban—an oral, direct factor Xa inhibitor—in patients undergoing major orthopaedic surgery. Clin Pharmacokinet 2008;47(3):203–16. [30] Samama MM, Martinoli JL, LeFlem L, et al. Assessment of laboratory assays to measure rivaroxaban—an oral, direct factor Xa inhibitor. Thromb Haemost 2010;103(4):815–25. [31] Smythe MA, Fanikos J, Gulseth MP, et al. Rivaroxaban: practical considerations for ensuring safety and efficacy. Pharmacotherapy 2013;33(11):1223–45. [32] Harenberg J, Marx S, Erdle S, et al. Determination of the anticoagulant effects of new oral anticoagulants: an unmet need. Expert review of hematology 2012;5(1): 107–13. [33] Wong PC, Watson CA, Crain EJ. Arterial antithrombotic and bleeding time effects of apixaban, a direct factor Xa inhibitor, in combination with antiplatelet therapy in rabbits. J Thromb Haemost 2008;6(10):1736–41. [34] Ehrlich HJ, Henzl MJ, Gomperts ED. Safety of factor VIII inhibitor bypass activity (FEIBA): 10-year compilation of thrombotic adverse events. Haemophilia 2002;8(2):83–90. [35] Hsia CC, Chin-Yee IH, McAlister VC. Use of recombinant activated factor VII in patients without hemophilia: a meta-analysis of randomized control trials. Ann Surg 2008;248(1):61–8. [36] Crowther MA, Warkentin TE. Managing bleeding in anticoagulated patients with a focus on novel therapeutic agents. J Thromb Haemost 2009;7(Suppl 1): 107–10. [37] Kcentra (Prothrombin Complex Concentrate, Human) [Package Insert]. Kankakee, IL, USA: CSL -Behring LLC; Prescribing Information; 2013. [38] Quinlan DL, Eikelboom JW, Weitz JI. 4-factor prothrombin complex concentrate for urgent reversal of vitamin K antagonists in patients with major bleeding. Circulation 2013;128(11):1179–81. [39] FEIBA (Factor VII Inhibitor Bypassing Activity) [Package Insert]. Westlake Village, CA, USA: Baxter Healthcare Corporation; Prescribing Information; 2013. [40] van Ryn J, K.-E.M., Clemens A. The successful reversal of dabigatran induced bleeding by coagulation factor concentrates in a rat tail bleeding model do not correlate with ex vivo markers of anticoagulation. 53rd ASH Annual Meeting and Exposition; 2011 San Diego, CA. [41] Pragst I, Zeitler SH, Doerr B, et al. Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model. J Thromb Haemost 2012;10(9):1841–8. [42] Zhou W, Schwarting S, Illanes S, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke 2011;42(12):3594–9. [43] Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebocontrolled, crossover study in healthy subjects. Circulation 2011;124(14):1573–9.

382

M.P. Miller et al. / American Journal of Emergency Medicine 32 (2014) 375–382

[44] Bernstein RA, Alberts MJ, Garcia DA. Letter by Bernstein et al regarding article, “reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects”. Circulation 2012;125(16):e614 [author reply e6]. [45] Marlu R, Hodaj E, Paris A, et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost 2012;108(2):217–24. [46] Khoo TL, Weatherburn C, Kershaw G, et al. The use of FEIBA ((R)) in the correction of coagulation abnormalities induced by dabigatran. Int J Lab Hematol 2013 Apr;35(2):222–4. http://dx.doi.org/10.1111/ijlh.12005. [Epub 2012 Sep 28]. [47] van Ryn J, Sieger P, Kink-Eiband M, et al. Adsorption of dabigatran etexilate in water or dabigatran in pooled human plasma by activated charcoal in vitro 51st ASH Annual Meeting and Exposition New Orleans, LA; 2009. [48] Kaatz S, Kouides PA, Garcia DA, et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol 2012;87(Suppl 1):S141–5. [49] Marlu R, Hodaj E, Pernod G. Letter by Marlu et al regarding article, “reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects”. Circulation 2012; 125(16):e615 [author reply e6]. [50] Perzborn E, Tinel H. Prothrombin complex concentrate reverses the effects of highdose rivaroxaban in rats. Journal of Thrombosis and Haemostasis 2009;7(379).

[51] Godier A, Miclot A, Le Bonniec B, et al. Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology 2012;116(1):94–102. [52] Gruber A, Marzec U, Holcomb J. Potential of activated prothrombin complex concentrate and activated factor VII to reverse the anticoagulant effects of rivaroxaban in primates. 50th ASH Annual Meeting and Exposition San Francisco, CA; 2008. [53] Food and Drug Administration. Advisory committee briefing book. rivaroxaban. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/ Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM138385. [54] Weber BJ, Kjelland CB. The use of tranexamic acid for trauma patients? CJEM 2012;14(1):53–6. [55] Sammartino G, Marenzi G, Miro A, et al. Local delivery of the hemostatic agent tranexamic acid in chronically anticoagulated patients. J Craniofac Surg 2012;23(6):e648–52. [56] Aniara. Dabigatran (Pradaxa) Plasma Calibrator Package Inset. http://www.anaira. com/pdf/INS-A222801.pdf; 2013. (11/25/2013). [57] Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013;121(18):3554–62. [58] Yeh CH, Fredenburgh JC, Weitz JI. The real decoy: an antidote for factor Xa–directed anticoagulants. Circ Res 2013 Sep 27;113(8):954–7. http: //dx.doi.org/10.1161/CIRCRESAHA.113.302297.