Managing bleeding and emergency reversal of newer oral anticoagulants: a review for primary care providers.

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Managing Bleeding and Emergency Reversal of Newer Oral Anticoagulants: A Review for Primary Care Providers

DOI: 10.3810/hp.2014.10.1144

W. Frank Peacock IV, MD, FACEP Associate Chairman, Director of Research for Emergency Medicine, Baylor College of Medicine, Houston, TX

Abstract: The therapeutic landscape for anticoagulation management is undergoing a shift from the use of traditional anticlotting agents such as heparins and warfarin as the only options to the growing adoption of newer target-specific oral anticoagulants (TSOACs) with novel mechanisms of action. Dabigatran, the first TSOAC approved for use in the United States, is a direct competitive inhibitor of thrombin. It has predictable kinetics, with an elimination half-life of 12 to 17 hours in healthy volunteers. Apixaban and rivaroxaban are selective inhibitors of factor Xa, and also display first-order kinetics. In younger healthy individuals, apixaban has an apparent half-life of approximately 12 hours, whereas rivaroxaban has an elimination half-life of 5 to 9 hours. Understanding the pharmacologic properties of these newer drugs can lead to better insights regarding their respective safety and efficacy profiles and their application in clinical practice. Laboratory assessments have been developed to measure the anticoagulant efficacy of these newer agents. However, the results of these tests can be highly variable, and are therefore not always useful for monitoring the anticoagulation effects of these agents. In addition, several strategies have been documented for the potential reversal of the anticoagulant effects of these drugs, from the temporary discontinuation of an agent before elective surgery to suggested emergency procedures in the case of major bleeding events. New, specific reversal agents for dabigatran, apixaban, and rivaroxaban are currently being developed, and dabigatran has received fast-track designation from the US Food and Drug Administration. Until comprehensive clinical guidelines are developed, institutions involved in emergency care should establish their own procedures for the management of patients undergoing anticoagulation who require emergency treatment. These protocols should include appropriate laboratory testing to assess anticoagulant activity as part of the inpatient workup if time allows, and the potential use of hemodialysis, prohemostatic agents, and reversal agents when available. Keywords: anticoagulation therapy; apixaban; rivaroxaban; dabigatran

Anticoagulation Therapeutic Landscape

Correspondence: W. Frank Peacock IV, MD, FACEP, 1504 Taub Loop, Houston, TX 77030. Tel: 713-873-2626 E-mail: [email protected]

Warfarin, the mainstay of oral anticoagulant (OAC) therapy for 6 decades, retains an important role in reducing morbidity and mortality associated with atrial fibrillation (AF), and other indications, including venous thromboembolism (VTE). However, evidence drawn from a nationally representative sample including more than half of all retail pharmacies in the United States confirms that target-specific OACs (TSOACs) have made substantial inroads on the landscape of treatment of thromboembolic disease since US Food and Drug Administration (FDA) approval of the first such agent, dabigatran etexilate, in 2010.1,2 The TSOACs include the direct thrombin

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W. Frank Peacock IV

inhibitor dabigatran and the factor Xa inhibitors apixaban and rivaroxaban. These newer agents also benefit from stable pharmacokinetics, leading to predictable pharmacodynamics. Dabigatran has an elimination half-life of 12 to 17 hours in healthy volunteers.2 Apixaban and rivaroxaban also display firstorder kinetics. In younger healthy individuals, apixaban has an apparent half-life of approximately 12 hours,3 whereas rivaroxaban has an elimination half-life of 5 to 9 hours.4 A recent meta-analysis of 3 randomized phase 3 clinical trials compared the safety and efficacy of the TSOACs (apixaban, rivaroxaban, and dabigatran) versus warfarin in the setting of AF.5 The incidence of stroke or systemic embolism and the incidence of major bleeding were the primary efficacy and safety endpoints, respectively.5 The analysis of data from 50 578 patients indicated that TSOACs significantly decreased stroke or systemic embolism (2.8% vs 3.5%; odds ratio [OR], 0.82; 95% CI, 0.74–0.91; P , 0.001), death (6.0% vs 6.3%; OR, 0.88; 95% CI, 0.82–0.95; P = 0.001), and stroke (2.4% vs 3.0%; OR, 0.79; 95% CI, 0.71–0.88; P , 0.001).5 A subanalysis indicated that the observed reduction in the incidence of stroke was primarily driven by a reduction in hemorrhagic strokes (0.3% vs 0.8%; OR, 0.79; 95% CI, 0.71–0.88; P , 0.001).5 No significant difference was detected in the rates of major bleeding events, which occurred in 5.0% and 5.6% of patients in the TSOAC and warfarin groups, respectively (OR, 0.85; 95% CI, 0.69–1.05; P = 0.14 [random effects model]). Lower incidences of intracranial bleeding (0.6% vs 1.3%; P , 0.001) and higher rates of gastrointestinal bleeding (2.3% vs 1.3%; P = 0.036) were reported in the patients treated with TSOACs.5 All of the TSOACs are indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular AF (NVAF).3 Additionally, dabigatran2 and rivaroxaban3 are approved for the treatment and prevention of VTE, including deep vein thrombosis and pulmonary embolism. Results of another meta-analysis of 4 pivotal clinical trials (N = 71 683) comparing the TSOACs rivaroxaban, apixaban, edoxaban, and dabigatran with warfarin in patients with NVAF indicated that high-dose regimens of TSOACs significantly reduced stroke and systemic embolism events by 19% compared with warfarin, mainly owing to reductions in hemorrhagic stroke.6 High-dose TSOACs also significantly reduced all-cause mortality and intracranial hemorrhage, albeit with an increase in gastrointestinal bleeding (P = 0.04 vs warfarin) but no difference in the risk of myocardial infarction. The authors of the meta-analysis did not suggest that all TSOACs were the same or that the randomized trials were 76

homogeneous in design or execution, nor did they imply that any TSOAC was superior over the others. However, they emphasized that the TSOACs offer a choice when previously none existed, and that in contrast with the TSOACs, which do not require routine anticoagulation monitoring, warfarin’s efficacy depends on high-quality anticoagulation control as expressed by time in the therapeutic range, defined as international normalized ratio (INR) of 2.0 to 3.0. This level of control was achieved for no more than approximately two-thirds of the time in the pivotal trials.6,7 A recent meta-analysis of 4 randomized clinical trials with 7877 participants addressed the relative safety and efficacy of approved TSOACs (apixaban, rivaroxaban, and dabigatran), and assessed recurrent VTE or VTE-related death as the primary endpoint.8 The primary safety outcome was major bleeding. Therapy with TSOACs led to significantly lowered risk of recurrent VTE or VTE-related death compared with placebo/warfarin (OR, 0.25; 95% CI, 0.07–0.86).8 Importantly, all-cause mortality was significantly lower in the TSOAC group compared with placebo (OR, 0.38; 95% CI, 0.18–0.80). With regard to major bleeding, this metaanalysis found that major bleeding occurred in 0.5% of patients receiving TSOACs, versus 0.8% of patients receiving placebo/warfarin (OR, 0.88; 95% CI, 0.27–2.91).8 In regard to major bleeding, TSOAC therapy led to significantly higher rates of major or clinically relevant bleeding compared with placebo, (OR, 2.69; 95% CI, 1.25–5.77).8 When compared individually, each of the TSOACs tested led to significantly lower rates of recurrent VTE or VTE-related death compared with placebo. Overall, in comparison to placebo, the rates of major or clinically relevant bleeding events were higher with dabigatran and rivaroxaban, but not with apixaban.8 Uptake of TSOACs is likely to expand as clinicians consider the advantages over warfarin, such as the lack of a requirement for routine monitoring and the considerably fewer known drug–drug interactions than historically seen in warfarin. One area of possible concern with rivaroxaban and apixaban are interactions with drugs that are metabolized via common cytochrome P450 (CYP) enzyme pathways. Elevated blood levels of apixaban3 and rivaroxaban4 can result from concomitant dosing of effective dual inhibitors of the CYP3A4 and permeability glycoprotein (P-gp). Modest reductions in circulating dabigatran concentrations have been reported with concomitant use of P-gp inducers, whereas P-gp inhibitors were not reported to have a significant effect.2 Dabigatran is neither a substrate, inhibitor, nor inducer of CYP450 enzymes.2 Key warnings related to potential drug– drug interactions are presented in Table 1.

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Emergency Reversal of TSOACs

Although clinical guidelines offer recommendations for patients who are candidates for anticoagulant therapies, they do not address the reversal of TSOAC effects in the case of bleeding.9 With wider use of TSOACs, for which specific reversal agents are in development but not yet available, emergency department physicians and allied health care professionals must develop a consensus on approaches to management of the bleeding events that are the result of all anticoagulant therapies.

enzyme-controlling conversion of oxidized vitamin K to reduced vitamin K, which is necessary for the final synthesis of the vitamin K–dependent clotting factors II, VII, IX, and X in the liver.11 The TSOACs were designed to inhibit specific targets in the coagulation pathway. Dabigatran and its active metabolites are direct competitive inhibitors of thrombin,2 whereas rivaroxaban and apixaban are both competitive inhibitors of factor Xa.3,4

Anticoagulant Effects on the Clotting Cascade

All 3 TSOACs approved to date are administered in fixed doses, without a requirement for monitoring of anticoagulant activity. However, clinicians may need to determine the intensity of anticoagulation for the effective management of patients, such as before surgery or other invasive procedures, or in cases of bleeding, anticoagulant overdose, or deteriorating renal function constituting functional overdose.12 Functional overdose is a risk among patients who experience a decline in renal function during anticoagulant therapy, whereby a formerly appropriate TSOAC dose becomes excessive. The ingestion history (timing and possible dosage) can be critical information, because it can help elucidate the expected pharmacokinetic and pharmacodynamic concerns of the drug in question. In addition, because renal function can change over time, this parameter should be monitored in patients who may be at risk of renal injury.2 The dabigatran label advises a dose of 75 mg twice daily for patients with a creatinine clearance (CrCl) rate of 15 to 30 mL/min, and for lower CrCl rates, dabigatran is not recommended.2 The rivaroxaban label recommends a reduced dose of 15 mg once daily for patients with a CrCl rate of 15 to 50 mL/min,4 and the label for apixaban recommends halving the dose to

In vivo coagulation via the extrinsic pathway is triggered when tissue factor is exposed to factor VII or VIIa, with formation of an enzyme complex that initiates a series of reactions, culminating in the production of thrombin (Figure 1). Tissue factor/factor VIIa catalyzes the conversion of factor X to Xa, which subsequently converts prothrombin to thrombin (factor IIa) in the presence of factor Va and calcium. Thrombin amplifies the hemostatic response through activation of factors V, VIII, and XI; converts fibrinogen to fibrin; stabilizes the fibrin clot through activation of factor XIII; and activates platelets.10 The intrinsic pathway involves factors VIII, IX, XI, and XII (Hageman factor); prekallikrein; and high-molecular-weight kininogen. This pathway is generally activated when factor XII binds to negatively charged proteins, which have been exposed to the blood after tissue damage. Activated factor XII then sequentially activates factors XI, IX, and X, and then factor II (prothrombin to thrombin), thereby converting fibrinogen to fibrin. The anticoagulant effect of warfarin is mediated through inhibition of vitamin K epoxide reductase, the

Measuring Anticoagulant Effect

Table 1. Summaries of Known Drug–Drug Interactions of Concern With Approved TSOACs PI Update

Drug Interaction Warnings From PI

Apixaban

August 2014

Dabigatran2

August 2014

Rivaroxaban4

March 2014

• Blood levels of apixaban are elevated by strong dual inhibitors of CYP3A4 and P-gp; therefore the dose of apixaban should be reduced to 2.5 mg, or concomitant use should be avoided • Strong dual inducers of CYP3A4 and P-gp reduce blood levels of apixaban; therefore concomitant use should be avoided • Coadministration with antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID use can lead to increased bleeding risk • P-gp inducers, such as rifampin, reduce exposure to dabigatran; therefore, their concomitant use should be avoided • Should consider reducing dose, or avoiding dabigatran in patients receiving P-gp inhibitors, and whose CrCl rate is between 30 to 50 mL/min • Dabigatran is not recommended in patients who are receiving P-gp inhibitors, and whose CrCl rate is , 30 mL/min • Avoid concomitant use with: combined P-gp and strong CYP3 A4 inhibitors or inducers other anticoagulants

3

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Abbreviations: CrCl, creatinine clearance; CYP, cytochrome P450; NSAID, nonsteroidal anti-inflammatory drug; P-gp, permeability glycoprotein; PI, prescribing information. © Hospital Practice, Volume 42, Issue 4, October 2014, ISSN – 2154-8331 77 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

W. Frank Peacock IV


Figure 1. Coagulation cascade and point of effect of the common anticoagulants.

Adapted by permission from Macmillan Publishers Ltd: Nature Reviews Cardiology (Makaryus JN, Haperin JL, Lau JF. Oral anticoagulants in the management of venous thromboembolism. Nat Rev Cardiol. 2013;10:397–409), copyright (2013).

2.5 mg twice daily in patients with $ 2 of the following characteristics: age $ 80 years, body weight # 60 kg, serum creatinine level $ 1.5 mg/dL.3 The standard prothrombin time (PT)/INR assay used to assess warfarin anticoagulant activity does not provide meaningful results with the TSOACs, and the results could cause confusion in the care of patients receiving any of the newer agents. The prodrug dabigatran etexilate mesylate is converted by ubiquitous esterases to the direct thrombin inhibitor dabigatran, which inhibits both free and clot-bound fibrin.2,10 The anticoagulant activity of dabigatran can be assessed by measuring the activated partial thromboplastin time (aPTT); however, the dose response is curvilinear, with a varying relationship between drug level and anticoagulant effect. At peak therapeutic plasma concentrations of dabigatran, the aPTT is increased to 2 to 3 times control values, and at trough concentrations (12 hours after the last dose) it falls to approximately 1.3 times control values. After abrupt drug withdrawal following steady-state dosing, the aPTT returns to baseline within 24 hours; measurable improvement is evident within 4 to 6 hours.13 However, because the aPTT prolongation response plateaus at therapeutic dabigatran concentrations, the aPTT gives an approximate assessment, 78

which primarily indicates that little or no dabigatran is present and coagulation is becoming normalized. Although qualitative assessment of the anticoagulant activity of dabigatran can be provided by the aPTT test, the individual reagents used in these assays can vary in their sensitivity to dabigatran, thereby potentially complicating the clinical interpretation of the test results.14 The ecarin clotting time assay has a linear response to plasma dabigatran across the therapeutic range; an increase in measured ecarin clotting time correlates directly with dabigatran concentration.10 This test can be used to assess anticoagulant activity resulting from dabigatran.2 Additionally, the diluted thrombin time (measured using the HEMOCLOT direct thrombin inhibitor assay; HYPHEN BioMed, France) allows for a sensitive and linear measurement of dabigatran activity. Although it is certified in Europe, this test is currently not available in the United States. Rivaroxaban and apixaban, as competitive reversible antagonists of activated factor Xa, prevent conversion of prothrombin to thrombin.10 These agents inhibit both free factor Xa activity and factor Xa incorporated into the prothrombinase complex.10 Rivaroxaban has a half-life of 5 to 9 hours in healthy volunteers, with little accumulation on repeated




daily dosing.15 The anticoagulant effect of rivaroxaban can be assessed through the actual PT but not the INR.9 For the factor Xa inhibitor rivaroxaban, PT is considered the best assessment of anticoagulant activity.16 However, none of the currently available PT reagents are very sensitive to apixaban. Currently, this leaves the anti-Xa assay as the only reasonable test to assess apixaban’s anticoagulant activity.17 Unfortunately, this test is not widely available, and rarely can provide the needed results within a useful timeframe. Standardized drug-specific anti-Xa assays can be used to measure the anticoagulant activity of rivaroxaban and apixaban. The anti-Xa assay uses a factor Xa chromogenic substrate; the color released is proportional to the amount of factor Xa. When a known quantity of factor Xa is added to plasma containing the factor Xa inhibitor, the amount of factor Xa–inhibitory activity in the plasma is determined from a standard curve.10 Unlike the indirect factor Xa inhibitor anticoagulants (heparins, fondaparinux), the direct factor Xa inhibitors do not require antithrombin for measurement, but they do require the generation of a standard curve using the drug in question.10 Although currently these assessments are not considered to be cost-effective, and are of limited utility in outpatient settings, assays are in development for monitoring the therapeutic effect of TSOACs in the clinical setting.18

Reversing Anticoagulant Effect

In patients undergoing anticoagulation therapy who must undergo elective invasive procedures, the risk of bleeding can usually be minimized through preventive strategies, including selection of the appropriate agent and dose before, during, and after the intervention; appropriate timing of anticoagulant withdrawal before, and reinstatement after, the procedure; monitoring for early signs and symptoms of bleeding; and laboratory monitoring as indicated.9,19 In the primary care setting, initial evaluation of a patient with TSOAC-associated bleeding involves determination of the severity of the event and the timing of the last dose of the TSOAC in question.20 In addition, identifying the source of the bleeding is a priority, along with appropriate procedures to bring the bleeding under control.20 Finally, renal function tests should be ordered to gain a better understanding of the expected clearance kinetics of the agent in question.20 Minor bleeding events, including epistaxis or bleeding from the gums, can often be resolved by simply withholding the next few doses of the TSOAC.20 For bleeds of moderate intensity, such as gastrointestinal bleeds, the approach should begin with withholding the anticoagulant agent, and include supportive care (circulatory support with fluids and

appropriate transfusion of blood products).20 Serious bleeding events generally represent medical emergencies, and if time and resources permit, patients will benefit from the involvement of an informed health care team and consultation with relevant specialists in cardiology, hematology, gastroenterology, and surgery, as needed.20

Summary of Steps to Evaluate and Manage a TSOAC-Related Bleeding Event20

• Assess the severity of the bleeding event • Withhold the next few doses of the TSOAC – 1 or 2 doses for minor bleeding events – As needed for more serious bleeding events • Identify the source of the bleeding and initiate appropriate procedures to control the bleeding event • Provide supportive care (fluid and blood products as needed)

However, in emergent situations when the patient has severe bleeding, experienced trauma, or has an unanticipated need for invasive procedures or surgery, clinicians must develop a comprehensive management plan extending to reversal of anticoagulant effect. Although the immediate priority is controlling bleeding, the risk of thrombosis becomes increasingly important in longer-term management.19 The OAC effect can be reversed through neutralizing or removing the drug, or inducing hemostasis independently of direct antagonism of the anticoagulant agent.19 Approaches to reversing anticoagulant activity include withdrawal of anticoagulant, administration of a specific reversal agent, and administration of clotting factor substitutes.9 Any measures taken should account for the duration of effect of both the OAC and the reversal agent administered. Although specific reversal agents are not currently clinically approved, the potential for rebound anticoagulation must be considered if the duration of the OAC effect exceeds that of the reversal agent.19 Notwithstanding the known drawbacks of warfarin therapy, a multitarget mode of action allows for a variety of approaches and a standardized protocol to reverse this agent’s anticoagulant effect.21,22 The main objective is to increase the concentration of vitamin K–dependent clotting factors.9 Time to onset and offset of warfarin’s anticoagulant effect is determined by the elimination half-life of the R- and S-isomers of the drug (45 and 29 hours, respectively) and of the vitamin K–dependent clotting factors: factor II (42–72 hours), factor VII (4–6 hours), factor IX (21–30 hours), and factor



W. Frank Peacock IV

X (27–48 hours).21 Within this considerable range, the long half-life of factor II is responsible for a major part of the lag between warfarin initiation and dose adjustment or discontinuation and the time when a clinical effect becomes apparent. Pharmacologic approaches to reversal include vitamin K (phytonadione), fresh frozen plasma, prothrombin complex concentrates (PCCs), and recombinant factor VIIa (rFVIIa). Vitamin K does not provide immediate reversal of warfarin’s anticoagulant activity, but rather requires several hours to days. Because as a group the TSOACs have short half-lives, clinical support and observation may be sufficient for most patients. However, the elimination half-lives and anticoagulant effects of the TSOACs are prolonged in patients with impaired renal function, and this effect is greatest with dabigatran, which is more dependent on renal elimination than the other TSOACs.19 Pharmacologic reversal must be tailored to the individual agent, taking account of the drug profile, the urgency of the clinical situation, and the severity of bleeding. Clinicians attempting TSOAC reversal must consider the specific drug’s mechanism of action, its clearance mechanisms, and its elimination half-life.9 In general, if the procedure in question is considered elective, then the minimum time between the last TSOAC dose and the procedure should be $ 24 hours. On the other hand, when faced with a medical emergency, patient needs will dictate the course of action, and if medically indicated, the surgeons should proceed as necessary. Under these circumstances, generalized reversal and supportive therapies will be provided as needed.

An additional option that will help prevent absorption of a drug from the gastrointestinal tract, and therefore lower total exposure, is the use of activated charcoal in patients in whom the ingestion was recent (within 6 hours). This approach has been used successfully with apixaban in healthy volunteers.23 Currently available approaches for the reversal of TSOAC actions are presented in Table 2. For none of the TSOACs has a reversal agent been approved. For dabigatran, emergent dialysis may be considered in circumstances such as renal failure or overdose, wherein a prolonged effect may result; approximately 57% of the total drug in circulation can be removed after 4 hours of hemodialysis.2 Prothrombin complex concentrates are pooled plasma products usually combining either 3 or 4 vitamin K–dependent clotting factors. Second-generation PCCs, which contain both procoagulant and anticoagulant factors, are believed to preserve homeostasis and reduce the risk of thrombosis. Evidence from a recent meta-analysis24 shows that the requirement for PCCs during a major bleeding event was not different among patients treated with dabigatran and those treated with warfarin. Results presented at the XXIV Congress of the International Society for Thrombolysis and Haemostasis in 2013 demonstrated that both 4-factor and 3-factor PCCs shortened the PT in healthy volunteers treated with rivaroxaban.25 The 4-factor PCC more effectively reduced mean PT, whereas the 3-factor PCC more effectively reversed rivaroxaban-induced changes in endogenous thrombin potential.25 Therefore, the authors suggested that the discrepancy in results might reflect the presence of

Table 2. Emergency Measures Appropriate for Currently Approved Anticoagulants Anticoagulant

Specific Reversal Agents?

Supportive Reversal Therapy

Warfarin Dabigatran

Vitamin K (phytonadione) None available2

Rivaroxaban

None available4

Apixaban

None available3

Fresh frozen plasma and PCC21 aPCCs (eg, FEIBA or rFVIIa, or concentrates of coagulation factors II, IX, or X) may be considered2 Administration of platelet concentrates in cases where thrombocytopenia is present or long-acting antiplatelet drugs have been used2 Dialysis may be considered if clinical situations warrant use and prolonged effect is anticipated2 Note: The above agents/strategies have not been adequately evaluated in clinical trials2 Not dialyzable owing to high protein binding4 Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban4 Administration of PCCs has demonstrated some reversal of PT prolongation in healthy volunteers4 Note: The use of aPCC or rFVIIa has not been adequately evaluated in clinical trials4 Not dialyzable owing to high protein binding Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of apixaban3 Note: The use of other procoagulant reversal agents such as aPCC or rFVIIa has not been adequately evaluated in clinical trials3 Administration of activated charcoal at 2 and 6 hours after ingestion may help to reduce the amount of drug absorbed into the blood after overdose or accidental ingestion3

9

Abbreviations: aPCC, activated prothrombin complex concentrates; FEIBA, factor VIII inhibitor bypassing activity; PCC, prothrombin complex concentrates; PT, prothrombin time; PTT, partial thromboplastin time; rFVIIa, recombinant factor VIIa.

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Table 3. Comparative Strategies for the Development of Specific TSOAC Reversal Agents TSOAC

Mechanism of Action

Specific Reversal Agents Under Development

Dabigatran

Dabigatran and its acyl glucuronides are direct competitive inhibitors of thrombin2 Selective inhibitors of FXa3,4

A specific monoclonal Fab antibody fragment that binds dabigatran with high affinity, and reverses dabigatran inhibition of thrombin within 5 minutes of infusion26 Andexanet alfa is a recombinant human FXa molecule that is modified to lack catalytic activity. However, it retains high-affinity binding to direct FXa inhibitors27 Mass-action sink effect through binding of TSOACs, resulting in the reversal of FXa inhibitor–mediated anticoagulation in preclinical and early clinical studies27

Apixaban Rivaroxaban


Abbreviations: Fab, fragment antigen-binding; FXa, factor Xa; TSOAC, target-specific oral anticoagulant.

heparin in the 4-factor PCC and the absence of factor VII in the 3-factor PCC.25 Transfusions with PCCs are expensive and not commonly used. As a result, clinical outcomes with this procedure have not been extensively studied. If time is available, consultation with a coagulation expert should be considered. However, in the case of a dire emergency, the treating physician must proceed with immediate therapy. The anticoagulant effect of apixaban can be expected to persist for approximately 24 hours after the last dose (ie, ∼2 half-lives); no reversal agent has been established and a specific antidote is not available. Use of procoagulant agents such as PCCs, activated PCCs, or rFVIIa may be considered but has not been evaluated in clinical studies.3 Neither of the factor Xa inhibitors is dialyzable because of high plasma protein binding.3,4,21 Novel specific reversal agents for the approved TSOACs are under development (Table 3), and have demonstrated good results in early trials. Although their clinical use is not expected to be widespread owing to the limited number of serious bleeding events associated with these drugs, these reversal agents will allow physicians to safely and quickly respond to any bleeding event emergency. These agents include a novel monoclonal antibody fragment that specifically binds dabigatran, thereby blocking its inhibition of thrombin,26 and an engineered version of human factor Xa, which lacks catalytic activity but does compete for the binding of factor Xa inhibitors.27 The European Heart Rhythm Association recently published a practical guide that was developed to help physicians in the use of the different new OACs. An Executive Summary including recommendations for several clinical scenarios can be a useful source for additional information.20

Conclusion

Until evidence allows the formulation of comprehensive clinical guidelines, institutions should establish procedures for the management of anticoagulated patients requiring emergency treatment, whether for drug-related bleeding or

because of an unanticipated need for invasive procedures. The plan should cover appropriate laboratory testing assessment of anticoagulant activity for inpatients if possible, use of hemodialysis, prohemostatic agents, and choice of reversal agent if available.

Acknowledgments

The author acknowledges the writing and editorial assistance of Rosemary Perkins of Envision Scientific Solutions, whose services were funded by Boehringer Ingelheim Pharmaceuticals, Inc. The author meets all criteria for authorship as recommended by the International Committee of Medical Journal Editors, was fully responsible for all content and editorial decisions, and was involved in all stages of manuscript development. The author received no compensation related to the development of the manuscript. The author was fully responsible for all content and editorial decisions, was involved at all stages of manuscript development and has approved the final version of the review that reflects the authors’ interpretation and conclusions. Medical writing assistance, supported financially by Boehringer Ingelheim Pharmaceuticals, Inc., was provided by Rosemary Perkins of Envision Scientific Solutions during the preparation of this review. Boehringer Ingelheim Pharmaceuticals, Inc. was given the opportunity to check the data used in the manuscript for factual accuracy only.

Conflict of Interest Statement

Dr. Peacock has obtained research grants from Abbott Laboratories, Alere, Banyan Biomarkers, Inc, Cardiorentis AG, Portola Pharmaceuticals, Inc., F. Hoffmann-La Roche Ltd, and The Medicines Company; served as a consultant for Alere, BG Medicine, Inc., Beckman Coulter, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Cardiorentis AG, Instrumentation Laboratory, Janssen Pharmaceuticals, Inc., Prevencion Inc., The Medicines Company, and ZS Pharma, Inc.; and has ownership interests in Comprehensive Research Associates, LLC, and Emergencies in Medicine, LLC.


W. Frank Peacock IV


References 1. Kirley K, Qato DM, Kornfield R, Stafford RS, Alexander GC. National trends in oral anticoagulant use in the United States, 2007 to 2011. Circ Cardiovasc Qual Outcomes. 2012;5(5):615–621. 2. Pradaxa (dabigatran) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2014. 3. Eliquis (apixaban) [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company; 2014. 4. Xarelto (rivarixaban) [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2014. 5. Capodanno D, Capranzano P, Giacchi G, Calvi V, Tamburino C. Novel oral anticoagulants versus warfarin in non-valvular atrial fibrillation: a meta-analysis of 50,578 patients. Int J Cardiol. 2013;167(4):1237–1241. 6. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383(9921):955–962. 7. Larsen TB, Lip GY. Warfarin or novel oral anticoagulants for atrial fibrillation? Lancet. 2014;383(9921):931–933. 8. Sardar P, Chatterjee S, Mukherjee D. Efficacy and safety of new oral anticoagulants for extended treatment of venous thromboembolism: systematic review and meta-analyses of randomized controlled trials. Drugs. 2013;73(11):1171–1182. 9. Peacock WF, Gearhart MM, Mills RM. Emergency management of bleeding associated with old and new oral anticoagulants. Clin Cardiol. 2012;35(12):730–737. 10. Konkle BA. Monitoring target specific anticoagulants. J Thromb Thrombolysis. 2013;35(3):387–390. 11. Kalus JS. Pharmacologic interventions for reversing the effects of oral anticoagulants. Am J Health Syst Pharm. 2013;70(10 Suppl 1): S12–S21. 12. Baglin T. The role of the laboratory in treatment with new oral anticoagulants. J Thromb Haemost. 2013;11(Suppl 1):122–128. 13. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124(14):1573–1579. 14. Adcock DM, Gosselin R, Kitchen S, Dwyre DM. The effect of dabigatran on select specialty coagulation assays. Am J Clin Pathol. 2013;139(1):102–109. 15. Eriksson BI, Kakkar AK, Turpie AG, et al. Oral rivaroxaban for the prevention of symptomatic venous thromboembolism after elective hip and knee replacement. J Bone Joint Surg Br. 2009;91(5):636–644. 16. Samama MM, Contant G, Spiro TE, et al. Laboratory assessment of rivaroxaban: a review. Thromb J. 2013;11(1):11.

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17. Douxfils J, Chatelain C, Chatelain B, Dogné JM, Mullier F. Impact of apixaban on routine and specific coagulation assays: a practical laboratory guide. Thromb Haemost. 2013;110(2):283–294. 18. Garcia D, Barrett YC, Ramacciotti E, Weitz JI. Laboratory assessment of the anticoagulant effects of the next generation of oral anticoagulants. J Thromb Haemost. 2013;11(2):245–252. 19. Dager WE. Developing a management plan for oral anticoagulant reversal. Am J Health Syst Pharm. 2013;70(10 Suppl 1):S21–S31. 20. Heidbuchel H, Verhamme P, Alings M, et al. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J. 2013;34(27):2094–2106. 21. Nutescu EA. Oral anticoagulant therapies: balancing the risks. Am J Health Syst Pharm. 2013;70(10 Suppl 1):S3–S11. 22. Parra MW, Zucker L, Johnson ES, et al. Dabigatran bleed risk with closed head injuries: are we prepared? J Neurosurg. 2013;119(3):760–765. 23. Wang X, Mondal S, Wang J, et al. Effect of activated charcoal on apixaban pharmacokinetics in healthy subjects. Am J Cardiovasc Drugs. 2014;14(2):147–154. 24. Majeed A, Hwang HG, Connolly SJ, et al. Management and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation. 2013;128(21):2325–2332. 25. Levi M, Moore T, Castillejos CF, et al. Effects of three-factor and fourfactor prothrombin complex concentrates on the pharmacodynamics of rivaroxaban. Paper presented at: XXIV Congress of the International Society for Thrombolysis and Haemostasis; June 29–July 4, 2013; Amsterdam, The Netherlands. Abstract OC 36.5. 26. Glund S, Stangier J, Schmohl M, et al. A specific antidote for dabigatran: Immediate, complete and sustained reversal of dabigatran induced anticoagulation in healthy male volunteers. Paper presented at: American Heart Association Scientific Sessions 2013; November 17–19, 2013; Dallas, TX. Abstract 17765. 27. Crowther M, Vandana M, Michael K, Genmin L, et al. A phase 2 randomized, double-blind, placebo-controlled trial demonstrating reversal of rivaroxaban-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), an antidote for Fxa inhibitors. Paper presented at: 55th American Society of Hematology Annual Meeting and Exposition; December 7–10, 2013; New Orleans, LA. Abstract 3636.


Newer oral anticoagulants.

Newer Oral Anticoagulants: Stroke Prevention and Pitfalls.

Oral anticoagulants and status of antidotes for the reversal of bleeding risk.

Management of bleeding and reversal strategies for oral anticoagulants: clinical practice considerations.

Potential antidotes for reversal of old and new oral anticoagulants.

Novel oral anticoagulants and reversal agents: Considerations for clinical development.

Direct oral anticoagulants and the bleeding patient.

Strategies for urgent reversal of target-specific oral anticoagulants.

Reversal agents in development for the new oral anticoagulants.

Managing a Rivaroxaban Bleed: Understanding the Difficulties in Acute Reversal of the New Oral Anticoagulants through a Case Report.

Practical considerations in emergency management of bleeding in the setting of target-specific oral anticoagulants.

Bleeding complications from the direct oral anticoagulants.

Reversal of the novel oral anticoagulants dabigatran, rivoraxaban, and apixaban.

Point-of-care testing for emergency assessment of coagulation in patients treated with direct oral anticoagulants.

Newer anticoagulants for non-valvular atrial fibrillation.

Traditional Anticoagulants and Hair Loss: A Role for Direct Oral Anticoagulants? A Review of the Literature.

Recurrent Thrombosis in Patients with Antiphospholipid Syndrome Receiving Newer Oral Anticoagulants: A Case Report and Review of Literature.

Managing diagnostic uncertainty in primary care: a systematic critical review.

[Management of new oral anticoagulants in gastrointestinal bleeding and endoscopy].

Outcomes Associated With Prothrombin Complex Concentrate for International Normalized Ratio Reversal in Patients on Oral Anticoagulants With Acute Bleeding.

A mouse bleeding model to study oral anticoagulants.

Nonclinical Safety Assessment of PER977: A Small Molecule Reversal Agent for New Oral Anticoagulants and Heparins.

The Reversal of Direct Oral Anticoagulants in Animal Models.

Direct-Acting Oral Anticoagulants: Practical Considerations for Emergency Medicine Physicians.