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Management of Severe Bleeding in Patients Treated With Oral Anticoagulants

Proceedings Monograph From the Emergency Medicine Cardiac Research and Education Group-International Multidisciplinary Severe Bleeding Consensus Panel October 20, 2018

Gibler, W. Brian MD*; Racadio, Judy M. MD; Associate Editor; Hirsch, Amy L. Assistant Editor; Roat, Todd W. Production & CME Manager

doi: 10.1097/HPC.0000000000000181
Review Articles
Open

In this Emergency Medicine Cardiac Research and Education Group (EMCREG)-International Proceedings Monograph from the October 20, 2018, EMCREG-International Multidisciplinary Consensus Panel on Management of Severe Bleeding in Patients Treated With Oral Anticoagulants held in Orlando, FL, you will find a detailed discussion regarding the treatment of patients requiring anticoagulation and the reversal of anticoagulation for patients with severe bleeding. For emergency physicians, critical care physicians, hospitalists, cardiologists, internists, surgeons, and family physicians, the current approach and disease indications for treatment with anticoagulants such as coumadin, factor IIa, and factor Xa inhibitors are particularly relevant. When a patient treated with anticoagulants presents to the emergency department, intensive care unit, or operating room with severe, uncontrollable bleeding, achieving rapid, controlled hemostasis is critically important to save the patient’s life. This EMCREG-International Proceedings Monograph contains multiple sections reflecting critical input from experts in Emergency Cardiovascular Care, Prehospital Emergency Medical Services, Emergency Medicine Operations, Hematology, Hospital Medicine, Neurocritical Care, Cardiovascular Critical Care, Cardiac Electrophysiology, Cardiology, Trauma and Acute Care Surgery, and Pharmacy. The first section provides a description of the current indications for the treatment of patients using oral anticoagulants including coumadin, the factor IIa (thrombin) inhibitor dabigatran, and factor Xa inhibitors such as apixaban and rivaroxaban. In the remaining sections, the treatment of patients presenting to the hospital with major bleeding becomes the focus. The replacement of blood components including red blood cells, platelets, and clotting factors is the critically important initial treatment for these individuals. Reversing the anticoagulated state is also necessary. For patients treated with coumadin, infusion of vitamin K helps to initiate the process of protein synthesis for the vitamin K–dependent coagulation proteins II, VII, IX, and X and the antithrombotic protein C and protein S. Repletion of clotting factors for the patient with 4-factor prothrombin complex concentrate, which includes factors II (prothrombin), VII, IX, and X and therapeutically effective concentrations of the regulatory proteins (protein C and S), provides real-time ability to slow bleeding. For patients treated with the thrombin inhibitor dabigatran, treatment using the highly specific, antibody-derived idarucizumab has been demonstrated to reverse the hypocoagulable state of the patient to allow blood clotting. In May 2018, andexanet alfa was approved by the US Food and Drug Administration to reverse the factor Xa anticoagulants apixaban and rivaroxaban in patients with major bleeding. Before the availability of this highly specific agent, therapy for patients treated with factor Xa inhibitors presenting with severe bleeding usually included replacement of lost blood components including red blood cells, platelets, and clotting factors and 4-factor prothrombin complex concentrate, or if not available, fresh frozen plasma. The evaluation and treatment of the patient with severe bleeding as a complication of oral anticoagulant therapy are discussed from the viewpoint of the emergency physician, neurocritical and cardiovascular critical care intensivist, hematologist, trauma and acute care surgeon, hospitalist, cardiologist, electrophysiologist, and pharmacist in an approach we hope that the reader will find extremely practical and clinically useful. The clinician learner will also find the discussion of the resumption of oral anticoagulation for the patient with severe bleeding after effective treatment important because returning the patient to an anticoagulated state as soon as feasible and safe prevents thrombotic complications. Finally, an EMCREG-International Severe Bleeding Consensus Panel algorithm for the approach to management of patients with life-threatening oral anticoagulant–associated bleeding is provided for the clinician and can be expanded in size for use in a treatment area such as the emergency department or critical care unit.

President, EMCREG-International, Professor of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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Dear Colleagues,

The Emergency Medicine Cardiac Research and Education Group (EMCREG)-International was established in 1989 as an emergency medicine cardiovascular and neurovascular organization led by experts from the United States, Canada, and across the globe. We now have Steering Committee members from the United States, Canada, Australia, Belgium, Brazil, France, the Netherlands, New Zealand, Japan, Singapore, Sweden, and the United Kingdom. Now in our 30th year, we remain committed to providing you with the best educational programs and enduring material pieces possible. In addition to our usual Emergency Physician audience, we now reach out to our colleagues in Cardiology, Internal Medicine, Family Medicine, Hospital Medicine, and Critical Care with our EMCREG-International University of Cincinnati College of Medicine Office of Continuing Medical Education (CME)-accredited symposia and enduring materials.

In this EMCREG-International Proceedings Monograph from the October 20, 2018, EMCREG-International Multidisciplinary Consensus Panel on Management of Severe Bleeding in Patients Treated with Oral Anticoagulants held in Orlando, FL, you will find a detailed discussion regarding the treatment of patients requiring anticoagulation and the reversal of anticoagulation for patients with severe bleeding. For emergency physicians, critical care physicians, hospitalists, cardiologists, internists, surgeons, and family physicians, the current approach and disease indications for treatment with anticoagulants such as coumadin, factor IIa, and factor Xa inhibitors are particularly relevant. When a patient treated with anticoagulants presents to the emergency department, intensive care unit, or operating room with severe, uncontrollable bleeding, achieving rapid, controlled hemostasis is critically important to saving the patient’s life.

This EMCREG-International Proceedings Monograph contains multiple sections reflecting critical input from experts in Emergency Cardiovascular Care, Prehospital Emergency Medical Services, Emergency Medicine Operations, Hematology, Hospital Medicine, Neurocritical Care, Cardiovascular Critical Care, Cardiac Electrophysiology, Cardiology, Trauma and Acute Care Surgery, and Pharmacy. The first section provides a description of the current indications for treatment of patients using oral anticoagulants including coumadin, the factor IIa (thrombin) inhibitor dabigatran, and factor Xa inhibitors such as apixaban and rivaroxaban. In the remaining sections, the treatment of patients presenting to the hospital with major bleeding becomes the focus. The replacement of blood components including red blood cells, platelets, and clotting factors is the critically important initial treatment for these individuals. Reversing the anticoagulated state is also necessary. For patients treated with coumadin, infusion of vitamin K helps to initiate the process of protein synthesis for the vitamin K–dependent coagulation proteins II, VII, IX, and X and the antithrombotic protein C and protein S. Repletion of clotting factors for the patient with 4-factor prothrombin complex concentrate (4FPCCs), which includes factors II (prothrombin), VII, IX, and X and therapeutically effective concentrations of the regulatory proteins (proteins C and S), provides real-time ability to slow bleeding. For patients treated with the thrombin inhibitor dabigatran, treatment using the highly specific, antibody-derived idarucizumab has been demonstrated to reverse the hypocoagulable state for the patient to allow blood clotting. In May 2018, andexanet alfa was approved by the US Food and Drug Administration to reverse the factor Xa anticoagulants apixaban and rivaroxaban in patients with major bleeding. Before the availability of this highly specific agent, therapy for patients treated with factor Xa inhibitors presenting with severe bleeding usually included replacement of lost blood components including red blood cells, platelets, and clotting factors and 4FPCCs, or if not available, fresh frozen plasma (FFP). The evaluation and treatment of the patient with severe bleeding as a complication of oral anticoagulant therapy are discussed from the viewpoint of the emergency physician, neurocritical and cardiovascular critical care intensivist, hematologist, trauma and acute care surgeon, hospitalist, cardiologist, electrophysiologist, and pharmacist in an approach we hope that the reader will find extremely practical and clinically useful. The clinician learner will also find the discussion of the resumption of oral anticoagulation for the patient with severe bleeding after effective treatment important because returning the patient to an anticoagulated state as soon as feasible and safe prevents thrombotic complications. Finally, an EMCREG-International Severe Bleeding Consensus Panel algorithm for the approach to management of patients with life-threatening oral anticoagulant–associated bleeding is provided for the clinician and can be expanded in size for use in a treatment area such as the emergency department or critical care unit. Through this EMCREG-International Multidisciplinary Severe Bleeding Consensus Panel Monograph, clinicians can receive state of the art information which can significantly impact the care of their patients. It is our sincere hope that you will find this EMCREG-International Proceedings Monograph on the care of patients requiring anticoagulation and having associated severe bleeding useful to you in your daily practice as an emergency physician, intensive care physician, hospitalist, cardiologist, internist, and family physician. Instructions for obtaining CME credit from the University of Cincinnati College of Medicine Office of Continuing Medical Education are available at the conclusion of this January 2019 EMCREG-International Multidisciplinary Severe Bleeding Consensus Panel Proceedings Monograph. Thank you very much for your interest in EMCREG-International educational initiatives; we hope that you visit our website (www.emcreg.org) for future educational events and publications.

W. Brian Gibler, MD

President, EMCREG-International

Professor of Emergency Medicine

University of Cincinnati College of Medicine

Cincinnati, OH

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TABLE OF CONTENTS:

  • MANAGEMENT OF SEVERE BLEEDING IN PATIENTS TREATED WITH ORAL ANTICOAGULANTS
  • INTRODUCTION
  • ORAL ANTICOAGULANTS
    • Warfarin and Other Vitamin K Antagonists
    • Direct Oral Anticoagulants
    • Assessment of Anticoagulant Activity
  • ORAL ANTICOAGULANT-ASSOCIATED BLEEDING
    • Prevention of DOAC-Associated Bleeding
  • REVERSING THE ANTICOAGULANT EFFECT
    • Repletion of Vitamin K-Dependent Factors
    • Reversal of Direct Oral Anticoagulants
  • APPROACH TO MANAGEMENT OF DOAC-ASSOCIATED BLEEDING
  • PREPARATION AND ADMINISTRATION OF REVERSAL AGENTS AND ROLE OF THE PHARMACIST
  • INSTITUTIONAL PROCESSES FOR THE ADMINISTRATION OF REVERSAL AGENTS
  • PREHOSPITAL MANAGEMENT OF THE ANTICOAGULATED PATIENT WITH SEVERE BLEEDING
  • EMERGENCY EVALUATION AND TREATMENT OF THE ANTICOAGULATED PATIENT WITH SEVERE BLEEDING
    • Emergency Medicine Perspective on the Trauma Patient
    • Intracranial Hemorrhage
    • Abdominal and Chest Trauma
    • Gastrointestinal Bleeding
    • Mucosal Bleeding
  • CRITICAL CARE MANAGEMENT OF THE ANTICOAGULATED PATIENT WITH SEVERE BLEEDING
    • Management of the Anticoagulated Patient in the Perioperative Setting
    • Evaluation and Treatment of Postprocedural Bleeding in the Anticoagulated Cardiac Patient
    • Management of the Bleeding Patient in the Cardiovascular Critical Care Unit after Surgery/Cardiopulmonary Bypass and ECMO
    • Restarting Anticoagulant Therapy After Reversal to Prevent Thrombotic Complications
  • CONCLUSIONS AND FUTURE DIRECTIONS
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INTRODUCTION

There are multiple indications for chronic oral anticoagulation (OAC) in contemporary medical practice, including treatment and prevention of venous thromboembolic disease (VTE, inclusive of deep vein thrombosis and pulmonary embolism), primary and secondary prevention of stroke and systemic embolism in atrial fibrillation (AF), protection against thromboembolic events in patients with mechanical heart valves, and secondary prevention of major cardiac events in patients with coronary artery disease or peripheral artery disease. As clear as these indications are from an efficacy perspective, it is manifestly impossible to provide anticoagulation to a patient without raising that patient’s risk of bleeding. Even properly prescribed, well-controlled anticoagulation results in a nonphysiologic state in which spontaneous bleeding is more likely, and in which the briskness of blood loss from vessel injury is accelerated.

Management of severe bleeding in patients taking oral anticoagulants is complicated. Acute care physicians must be knowledgeable about the individual oral anticoagulant agents, the general management of anticoagulant-associated bleeding, and the strategies for effective use of factor repletion and specific reversal agents. With any oral anticoagulant, minor or “nuisance” bleeding is most common and can be managed without repletion or reversal. For major oral anticoagulant–associated bleeding, class-specific approaches should be used and the necessary treatment agents made readily available in the emergency department (ED), the intensive care unit (ICU), and the surgical suite. Because the reversal agents for the thrombin inhibitor dabigatran and the factor Xa (FXa) inhibitors apixaban and rivaroxaban are expensive, acute care physicians should be prudent in using these important new therapies.

In this monograph, the available oral anticoagulant agents and the current options for repletion or reversal of their anticoagulant effects are reviewed. An algorithm for reversal of severe bleeding in patients taking FXa inhibitors and other anticoagulants is presented. Strategies for management of the patient with anticoagulant-associated bleeding are discussed, beginning with prehospital care and continuing through the ED and inpatient critical care settings. Finally, the approach to restarting anticoagulant therapy after severe bleeding to prevent thrombotic complications is discussed.

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ORAL ANTICOAGULANTS

Warfarin and Other Vitamin K Antagonists

In the coagulation cascade, multiple clotting factors interact in a sequence of events that converge into a final common pathway that results first in the transformation of factor X into the active FXa. FXa then enzymatically converts prothrombin (factor II) into thrombin (factor IIa), which serves both to activate platelets and to convert fibrinogen into fibrin. Vitamin K metabolism is essential to the hepatic synthesis of carboxylated (functionally active) coagulation factors II, VII, IX, and X that, in turn, can bind calcium and phospholipid-containing surfaces. The vitamin K antagonists (VKAs) impair vitamin K metabolism, resulting in greatly diminished reserves of these specifically configured zymogen enzymes and subsequent decreased ability to form thrombus. Of note, however, vitamin K is also required to synthesize protein C and protein S, which serve crucial roles in counterbalancing the coagulation cascade by regulating the conversion of prothrombin into thrombin.

Warfarin, the most common VKA in use in the United States, has a direct circulating plasma half-life of 36–42 hours. However, the effective half-life approaches 96 hours and is dependent on the liver’s ability to recover synthetic function and produce prothrombin (factor II).1 There is significant variability in treatment effect with VKAs based on individual metabolism, drug interactions, and comorbid conditions; therefore, treatment with a VKA requires frequent monitoring and dose adjustment.

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Direct Oral Anticoagulants

Dabigatran is unique in the category of direct oral anticoagulants (DOACs) in that it is a direct thrombin inhibitor, binding to the active site of thrombin and preventing downstream thrombin-mediated platelet activation and fibrinogen conversion. Peak effect occurs within 3 hours of an oral dose,2 and the effective half-life after steady state ranges from 12 to 17 hours (Table 1).6 The drug is primarily cleared by renal-dependent mechanisms, resulting in increased anticoagulation as renal function decreases; therefore, drug dosing varies with renal function.7 It is the only DOAC cleared by hemodialysis, although it remains unclear whether hemodialysis has an impact on the clinical effect. Dabigatran is potentiated by drugs that inhibit P-glycoprotein (P-gp) metabolism, such as amiodarone, ketoconazole, clarithromycin, and verapamil, and is inhibited by rifampin and other P-gp inducers.7

TABLE 1

TABLE 1

The FXa inhibitors (currently consisting of apixaban, betrixaban, edoxaban, and rivaroxaban) directly inhibit FXa, which results in decreased conversion of prothrombin to thrombin.8–11 All FXa inhibitors undergo renal and hepatic elimination. The FXa inhibitors (other than edoxaban) are metabolized by both the P-gp and the cytochrome P450 3A4 (CYP3A4) systems. Potent inhibitors of both of these systems, such as ketoconazole, itraconazole, ritonavir, and clarithromycin, will potentiate their effects, whereas inducers of CYP3A4 and P-gp (such as rifampin, phenytoin, and carbamazepine) will inhibit their anticoagulant efficacy. DOACs should be used with caution in patients with kidney impairment and are not recommended in patients with severe liver disease.

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Assessment of Anticoagulant Activity

The degree of anticoagulation with VKAs like warfarin can be quickly measured with a prothrombin time and international normalized ratio (INR). On the other hand, each DOAC produces variable effects on the coagulation measurement assays commonly available in the clinical setting.2,12 None have a direct linear relationship with any of the readily available coagulation assays; at best, an abnormal test may be considered relatively specific for the ongoing presence of the anticoagulant, but the absence of abnormality is not sensitive for the absence of anticoagulant effect.13 In other words, one cannot rely on normal coagulation assays to exclude anticoagulation effects. The sole exception to this is the relationship between dabigatran (the direct thrombin inhibitor) and thrombin time and ecarin clotting time, which do offer quantitative assessment of dabigatran’s activity but are not usually available on a “stat” basis.2 Anti-FXa assays exist; however, they are not readily available in most hospitals and necessitate that the assay be calibrated specifically for each of the different FXa agents.14 If an anti-FXa level calibrated to a specific DOAC is negative, it might obviate the need for reversal in a patient with life-threatening bleeding. Because there is currently no widely available test to make that decision, FXa levels are generally not useful in the emergency setting. Thromboelastography (TEG) is still under investigation as an option to assess the anticoagulated trauma patient.15

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ORAL ANTICOAGULANT–ASSOCIATED BLEEDING

Many patients with nonvalvular AF who are treated with anticoagulants are older and frequently carry >1 comorbid diagnosis, such as renal insufficiency, that increases bleeding risk. The risk of a major bleeding event in AF patients treated with warfarin is 2%–3% per year.16,17 Above 75 years old, the risk of intracranial hemorrhage (ICH) in patients taking warfarin increases significantly.18 Use of a DOAC may decrease bleeding risk by ≥30% overall,3,18–20 may decrease ICH by as much as 60%,18 and significantly decreases the risk of fatal hemorrhage,20 in comparison to warfarin. Currently, there are no randomized trials that compare one DOAC to another. Only gastrointestinal (GI) hemorrhage is more common in DOAC-treated patients (with the exception of apixaban and the dabigatran 110 mg twice daily dose) than in those treated with warfarin, but these events are rarely fatal.21 On the other hand, mortality from warfarin-related ICH is around 40% within a month of the event.22 Significant bleeding events in patients treated with anticoagulants for VTE are less common because the patients tend to be younger and have fewer comorbidities. Given the aging demographics of the US population, more patients require anticoagulation therapy for nonvalvular AF each year. Similarly, the prevalence of VTE continues to rise, as does the acceptance of more aggressive VTE prophylaxis protocols. OAC-related bleeding is a regular occurrence in the ED, and its incidence will only continue to increase.

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Prevention of DOAC-Associated Bleeding

Prevention of DOAC-associated bleeding requires appropriate dosing based on (1) the particular DOAC being prescribed; (2) whether it is being used as a therapeutic or prophylactic therapy; and (3) the underlying comorbidities of the patient.

Renal insufficiency requires reduction of the DOAC dose to mitigate bleeding risk. The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY),23 Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism in Atrial Fibrillation (ROCKET AF),24 Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE),25 and Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation -Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48)26 trials, which evaluated dabigatran, rivaroxaban, apixaban, and edoxaban, respectively, versus warfarin all excluded patients with a reduced creatinine clearance [CrCl; RE-LY, ROCKET, and ENGAGE: <30 mL/min, ARISTOTLE: <25 mL/min, or creatinine (Cr) >2.5 mg/dL]. For non-valvular AF patients, rivaroxaban should be used at 15 mg/d with CrCl <50 mL/min, and apixaban should be used at 2.5 mg twice daily with 2 of 3 criteria: age ≥80, weight ≤60 kg, or Cr ≥1.5 mg/dL. Edoxaban should be used at 30 mg/d for patients with NVAF and CrCl ≤50 mL/min and for patients with DVT or PE and CrCl ≤50 mL/min, body weight ≤60 kg, or who use certain P-gp inhibitors. Dabigatran dose should be reduced to 75 mg twice daily in patients with CrCl 15–30 mL/min.

Other strategies to avoid the risk of bleeding include blood pressure control, shortening the duration of concomitant antiplatelet or nonsteroidal anti-inflammatory drug (NSAID) therapy, and minimizing alcohol use while on DOACs. In addition, it is important to assess, treat, and normalize causes of anemia in patients on DOACs.

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REVERSING THE ANTICOAGULANT EFFECT

Repletion of Vitamin K–Dependent Factors

A patient who is therapeutically anticoagulated on a VKA has impaired physiologic activity at the multiple steps in the cascade that require participation of the vitamin K–dependent factors. Vitamin K administration merely allows the resumption of production of carboxylated gamma-carboxyglutamic acid (Gla) domain and functionally active factors, and it takes hours to several days to re-establish physiologic levels. Although necessary, this is certainly not a sufficient response to management of ICH or other life-threatening hemorrhage. In fact, warfarin-related anticoagulation cannot be reversed. Instead, the levels of deficient factors must be repleted, and clinicians must not view vitamin K as a “reversal agent.”

Repletion can be accomplished in several ways. Traditionally, fresh frozen plasma (FFP) was the direct repletion method of choice, but its use is limited by time requirements for thawing and cross-matching, concern for volume overload, and limited efficacy. The superior alternative for repleting vitamin K–dependent factors quickly is administration of prothrombin complex concentrate (PCC). The PCCs are pooled, virus-inactivated concentrates of human clotting factors. Four-factor PCCs (4FPCCs) contain the vitamin K–dependent coagulation factors [II (prothrombin), VII, IX, and X], and therapeutically effective concentrations of coagulation regulatory proteins (proteins C and S). Three-factor PCCs do not contain factor VII. In the past, some authorities recommended combining 3-factor PCCs with recombinant factor VIIa although the need for this approach has not been specifically studied. The PCCs are indicated and most commonly used for warfarin reversal. There are suggestive data that in warfarin-associated ICH, PCCs reduce hematoma expansion more than FFP does,4 and PCCs are preferentially recommended in professional society guidelines.27

Repletion of vitamin K–dependent factors in warfarin-associated hemorrhage and reversal of anticoagulation effect as in the case of DOAC treatment strategies discussed below should be reserved for life-threatening events, such as exsanguinating blood loss and ICH (Tables 2 and 3). Two immediate concerns arise from precipitous removal of anticoagulation. The first is that patients who are therapeutically anticoagulated are treated for a good clinical reason, such as high risk of stroke associated with AF, previously demonstrated pathologic clot (e.g., VTE), or mechanical heart valve (warfarin only). When anticoagulation “protection” is suddenly removed, these patients immediately return to their baseline prothrombotic state. It is important to note that the patient should be left “unprotected” for as short a time as is clinically possible. The second concern is intuitive—a patient might receive more repletion than is needed. The “overshoot” thromboembolic complications are unusual after repletion but are more common after PCC administration than with FFP. There is lower risk with FFP simply because less factor is being administered. Such events are still uncommon (5%–10%) after use of PCCs and are dose dependent. For that reason, it is usually recommended that 4FPCC be given in 2 separate 25 IU/kg doses, with a clinical evaluation performed after the first infusion and consideration of omitting the second if the patient is stabilized.28

TABLE 2

TABLE 2

TABLE 3

TABLE 3

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Reversal of DOACs

Reversal agents for the direct thrombin inhibitor, dabigatran, and the FXa inhibitors, apixaban and rivaroxaban, are now approved in the United States. These agents are not hemostatic; rather, they reverse the effect of anticoagulants and are not dependent on repletion of factors, which is a critical distinction as compared to PCCs. In therapeutic anticoagulation with dabigatran, there is no deficiency of thrombin. Native thrombin is instead inhibited by the anticoagulant. Removing the effects of dabigatran frees up previously inhibited thrombin to participate meaningfully once again in coagulation. Likewise, patients treated with apixaban, betrixaban, edoxaban, or rivaroxaban have normal circulating levels of FX, but Xa is inhibited by the therapy.

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Dabigatran Reversal

Idarucizumab is a humanized monoclonal antigen binding fragment (Fab) antibody to which dabigatran has 350 times higher affinity than to thrombin.29 It has no intrinsic activity in the coagulation system, and it provides immediate, complete, and sustained reversal of the dabigatran effect. Idarucizumab is eliminated quickly, allowing early resumption of dabigatran therapy in clinically stable patients. The dose is 5 g in total, administered intravenously as 2 vials of 2.5 g in rapid succession. Patients with very high dabigatran levels may show evidence of a recurrence of anticoagulation activity between 12 and 24 hours after reversal due to drug re-entering the circulation from the extravascular space, but a repeat dose should probably only be given if there is concomitant increased bleeding.

The safety and efficacy of idarucizumab as a reversal agent specifically for dabigatran were demonstrated in the Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) study of 503 patients, 301 of whom had serious or life-threatening hemorrhage.30 The median maximum percentage reversal of dabigatran, on the basis of either the diluted thrombin time or the ecarin clotting time, was 100% [95% confidence interval (CI), 100–100]. Nearly half of these patients had GI bleeding, and one-third presented with ICH. The median time to the cessation of bleeding was 2.5 hours, but this must be viewed in the context of multimodal hemorrhage management. Idarucizumab (like andexanet alfa) is not a hemostatic agent. It merely neutralizes iatrogenic anticoagulation, so that bleeding can be managed promptly, with mechanical and other pharmacologic means as appropriate and with support from transfusion of blood products as needed.30

At 90 days in RE-VERSE AD, thromboembolic events had occurred in 6.3% of the patients reversed for hemorrhage. Over 90% of these complications occurred in patients who did not have reinitiation of anticoagulant therapy. There were no serious adverse safety signals.30 Idarucizumab was also studied for, and approved for, reversal of dabigatran anticoagulation before an intervention that required good hemostasis.30

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FXa Inhibitor Reversal

A class-specific antidote, andexanet alfa, has been evaluated in several pivotal studies (A Study in Older Subjects to Evaluate the Safety and Ability of Andexanet Alfa to Reverse the Anticoagulation Effect of Apixaban [ANNEXA-A], A Study in Older Subjects to Evaluate the Safety and Ability of Andexanet Alfa to Reverse the Anticoagulation Effect of Rivaroxaban [ANNEXA-R], and A Study in Patients With Acute Major Bleeding to Evaluate the Ability of Andexanet Alfa to Reverse the Anticoagulation Effect of Direct and Indirect Oral Anticoagulants (Extension Study) [ANNEXA-4]31,32). These trials resulted in Food and Drug Administration approval for this therapy in patients with major bleeding associated with the use of the FXa inhibitors apixaban or rivaroxaban. Andexanet alfa is a decoy FXa that lacks biologic activity in the coagulation cascade because of removal of the Gla domain. It also has a mutation in the catalytic domain that removes its intrinsic procoagulant activity.32 The agent competitively binds to the Xa inhibitor, but the dose of andexanet must be tailored to the molar concentration of the anticoagulant, and an infusion must be maintained to continue the competitive blockade of the anticoagulant. In ANNEXA-4, the bolus dose of andexanet was followed immediately with a 2-hour infusion to avoid rebound of Xa activity that otherwise occurs. The recommended dosing of andexanet alfa is based on the specific FXa inhibitor, the dose of FXa inhibitor, and time since the patient’s last dose of FXa inhibitor (Tables 4 and 5).5

TABLE 4

TABLE 4

TABLE 5

TABLE 5

The full study data from ANNEXA-4 included 249 adjudicated severe bleeds that could be evaluated for hemostatic efficacy. Although some patients did not demonstrate complete reversal of anti-Xa activity, 204 (82%; 95% CI, 77-87%) achieved "excellent" or "good" hemostasis. From a safety perspective, thrombotic events occurred in 34 patients (10%) during the 30-day follow-up period, 11 of which occurred during the first 5 days. Therapeutic anticoagulation had resumed in only 8 patients (2%) before a thrombotic event occurred.32 Andexanet is not currently being studied for reversal before invasive procedures.

Until andexanet alfa became available, PCCs served as a possible alternative for the management of life-threatening bleeding associated with anti-Xa treatment. The PCCs reverse abnormal laboratory parameters (prothrombin time and endogenous thrombin potential) in human volunteers after taking high doses of rivaroxaban and apixaban.33–35 This is not an intuitive approach in managing patients who do not have deficient levels of FXa or any of the other constituents of PCC. For this reason, treatment of anti-Xa–related bleeding with PCCs may be associated with a risk of postrepletion thromboembolic complications. Treatment with the combination of a specific reversal agent and PCCs can increase the risk of thrombotic complications; therefore, if a patient will be treated with andexanet alfa or idarucizumab, PCCs should only be administered using extreme caution while balancing the risk versus benefit ratio in the patient with severe bleeding.

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APPROACH TO MANAGEMENT OF ORAL ANTICOAGULANT–ASSOCIATED BLEEDING

Management of DOAC-associated bleeding involves 4 steps: review, repair, reverse or replete, and resume (Fig. 1).36

FIGURE 1

FIGURE 1

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Step 1

Review requires one to stop the anticoagulation, determine the time of the last dose, review concomitant medications, evaluate the patient’s comorbidities, assess for cardiac decompensation, order baseline laboratory values, investigate the source of bleeding, maintain organ perfusion, and evaluate for transfusion. It is also important to remember that a conservative approach may be all that is needed because DOACs have short half-lives,37,38 so stopping therapy may be sufficient in patients with minor bleeds. Removal of the oral anticoagulant with gastric lavage, oral charcoal, or dialysis (for dabigatran) has been suggested as an additional step in the management of these patients.36 However, DOACs are rapidly absorbed after oral administration, and activated charcoal can make airway management extremely difficult should the patient become unstable and makes endoscopy nearly impossible in patients with GI bleeding. Therefore, the use of activated charcoal should be limited to and used with caution in acute overdose situations. Because dabigatran is dialyzable, hemodialysis has been suggested as part of the treatment strategy for dabigatran-related bleeding. However, now that idarucizumab is available to bind dabigatran, there is likely no longer a role for dialysis.

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Step 2

Repair involves assessing the need for endoscopy, interventional radiology, or surgery and performing the appropriate procedure to stop the bleeding. These definitive measures to control the bleeding source should be initiated in parallel with repletion or reversal in patients with severe bleeding.

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Step 3

Reverse includes use of reversal agents. The specific reversal agents, idarucizumab for dabigatran and andexanet alfa for apixaban and rivaroxaban, may be used for life-threatening bleeding, emergency surgery, and delayed clearance and bleeding. Replete includes use of PCCs or FFP for severe VKA-associated bleeding.

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Step 4

Resume involves making an informed clinical decision about when to resume anticoagulant therapy based on the nature of the bleeding episode and the patient’s risk for a thromboembolic event.

Specific management of bleeding associated with DOAC use varies according to the severity of bleeding.

“Minor bleeding” includes ecchymosis, most epistaxis, mucosal bleeding, hematuria, and menorrhagia. Management of minor DOAC-associated bleeding consists of temporarily discontinuing the DOAC, using local measures to control the source of bleeding, providing supportive care and maintaining hemodynamic status, and then consideration of restarting the DOAC when the bleeding has subsided and the risk for thrombosis exceeds the risk of bleeding.

“Moderate bleeding” includes most upper GI bleeding (UGIB) and lower GI bleeding (LGIB). The DOAC should be discontinued at least temporarily and the patient monitored closely. The underlying bleeding source should be investigated and definitively treated. Extended DOAC withdrawal should be considered, and utilization of low-dose parenteral anticoagulant for patients at particularly high risk of thrombosis may be necessary to allow healing. Transfusion therapy with packed red blood cells (PRBCs) for symptomatic anemia and monitoring of renal function are essential.

“Major bleeding” is defined by the International Society of Thrombosis and Hemostasis as fatal bleeding, bleeding involving a critical area (brain, spinal cord, pericardial, intraocular, retroperitoneal, intraarticular, or intramuscular with compartment syndrome), any bleeding that results in a net drop of hemoglobin of ≥2 g/dL, or bleeding that requires the transfusion of ≥2 units of PRBCs.39 Major bleeding requires immediate withdrawal of any anticoagulant and antiplatelet drugs. Aggressive clinical monitoring and transfusion of PRBCs in response to proven/anticipated severe anemia are required. Interventions to identify and treat the bleeding source include endoscopy, interventional radiology, and/or surgery. Life-saving therapies, including inotropes, ventilation, and ICU admission, should be considered as needed. Reversal or repletion should be administered as appropriate.

It should be noted that transfusing platelets in the face of thrombocytopenia is different from giving platelets to overcome antiplatelet agent effects. For patients taking antiplatelet agents, the decision to transfuse platelets will vary with the actual platelet antagonist being used and the site of the bleeding. Transfusion of pooled platelets can mitigate the effects of clopidogrel and prasugrel; however, it has no effect on platelet inhibition from ticagrelor and its active circulating metabolite. There is evidence that platelet transfusion in patients taking antiplatelet agents may cause harm, particularly in patients with GI bleeding and ICH.40,41 Platelet transfusions in GI bleeding patients on antiplatelet therapy are associated with increased mortality without improvement in recurrent GI bleeding, major adverse cardiovascular events, or length of hospital stay.41 Platelet transfusions have also been associated with worse outcomes in patients with ICH who have been taking antiplatelet therapy.40 Platelets are immune cells that release inflammatory markers, bioactive lipids, and cytokines. Transfusion may contribute to transfusion-related lung injury and also carries an increased risk of thrombosis due to platelet activation in stored product, possibly leading to recurrent events such as acute coronary syndrome, ischemic stroke, and deep vein thrombosis.42 Therefore, platelet transfusion should be reserved for life-threatening bleeding.

An algorithm for the approach to management of patients with life-threatening oral anticoagulant–associated bleeding is presented in Figure 2.

FIGURE 2

FIGURE 2

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PREPARATION AND ADMINISTRATION OF REVERSAL AGENTS AND ROLE OF THE PHARMACIST

Pharmacists can assist with appropriate patient selection and reversal agent administration. Specifically, they can aid in estimating the half-life of an anticoagulant, interpreting available coagulation tests, and/or identifying drug interactions that may prolong anticoagulant clearance. Finally, pharmacists can indirectly assist in patient selection and reversal administration by providing education for hospital staff about the importance of documenting vital data such as anticoagulant dose, body weight, and drug levels, and about specifics of drug administration, such as the fact that andexanet alfa and idarucizumab require special care to ensure that the entire dose is administered rather than having residual drug remaining in the tubing.

Anticoagulant reversal agents need to be available around-the-clock and should be available to the departments most likely to need them without undue delay. Assuring “timely” availability of reversal agents, however, requires the consideration of multiple logistical matters such as agent storage (idarucizumab and andexanet need to be refrigerated), admixture (ie, each vial needs 3-5 minutes for reconstitution), “proper reconstitution technique,” and transport requiring hand delivery. As a result, although many reversal agents provide rapid normalization of bleeding times once the agent is infused, the time from order to administration may be substantial at upwards of 30–45 minutes.

Anticoagulant reversal agents are expensive, and their cost-effectiveness has not been established. An analysis of the drug cost in the context of the overall cost of ED and intensive care and patient outcomes has not yet been performed. The high cost of many of these reversal agents may drive hospitals to create policies that mandate these agents be dispensed by the pharmacy. What impact pharmacy-based dispensing may have on the time to reversal agent administration is unclear, but it is worth noting that this was likely how many of the agents were handled during clinical trials as investigational drugs and how many time-sensitive agents, such as alteplase for acute ischemic stroke, are currently handled. If the decision is made to stock reversal agents outside of pharmacy, a mechanism to ensure the pharmacy is informed when they are utilized is of the utmost importance to assure that an uninterrupted supply is available for patients.

A final role for pharmacy is to assure any adverse events associated with reversal agents be reported to the manufacturers and the Food and Drug Administration’s Safety Information and Adverse Event Reporting Program.

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INSTITUTIONAL PROCESSES FOR THE ADMINISTRATION OF ANTICOAGULANT REVERSAL AGENTS

Because administration of specific anticoagulation reversal agents is costly and time consuming, institutions should develop their own predefined objective guidelines for determining which patients qualify for administration of a reversal agent. Ideally, these guidelines should be developed by a multidisciplinary team, and there should be at least one subject matter expert who can interpret the available data and make informed decisions for patients who may benefit from reversal but do not fit the institution’s standard guidelines. Although this model may work well at large academic institutions, it is not possible at all community hospitals. Therefore, each institution must work on their own process improvements to identify and mitigate barriers to proper and efficient administration of anticoagulation reversal agents. Furthermore, in each individual case, the decision to treat relies on the determination by the treating clinician that (1) there is life-threatening hemorrhage; (2) the hemorrhage is likely due to drug-related coagulopathy; and (3) the case is not futile.

Timely administration of the reversal agent requires that the processes involved in drug preparation and patient care occur in a parallel, rather than serial, fashion. For example, as soon as a patient is identified as being a possible candidate for DOAC reversal, the caregivers who will be involved, such as the pharmacy, nursing, ED, and critical care teams, should be notified so when the decision to treat is made, all are prepared for efficient execution of care. Involvement of a pharmacist on the clinical team can facilitate communication with central pharmacy and ensure prompt admixture and delivery of drug. As the drug is being prepared, the pharmacist can verify proper administration by double checking the patient’s DOAC dose, weight, and CrCl, and the medical team can begin to gather equipment and prepare the patient for control of the bleeding source. Finally, it should be noted that the time to obtain the drug from central pharmacy may be prohibitive in some cases, such as with pericardial tamponade, in which the decision to take the patient to the operating room (OR) must be made very quickly.

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PREHOSPITAL MANAGEMENT OF THE ANTICOAGULATED PATIENT WITH SEVERE BLEEDING

Hemorrhage control is a key life-saving intervention expected of every level of Emergency Medical Services (EMS) providers, and identification of life-threatening bleeding is a component of the prehospital “primary survey.”43 This focus is especially relevant in trauma, where almost half of trauma-related prehospital deaths are due to hemorrhage,44 and transfusion delays as short as 10 minutes are associated with increased mortality.45 Rapid reversal of anticoagulation in traumatic brain injury (TBI) patients decreases ICH growth, which may improve outcomes.46 Life-threatening nontraumatic hemorrhage is also common, with spontaneous ICH and GI bleeding being most prevalent.47–50 Almost 50% of EMS calls are for older adults51 and the use of anticoagulants in older adults with head trauma is common.52 As the population ages and the use of FXa inhibitors and other anticoagulants increases, prehospital treatments for hemorrhage control must evolve to meet patient needs.

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Current Prehospital Hemorrhage Control

Most external bleeding is adequately controlled with basic maneuvers, including simple bandages and direct pressure. Bandages impregnated with hemostatic agents offer advantages over simple gauze, especially in coagulopathic patients.53 Tourniquets, applied by the lay public or trained prehospital personnel, are effective in controlling significant extremity bleeding with few complications and significantly improved mortality.54,55

Civilian use of tranexamic acid (TXA) has increased since publication of the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH-2) study results.56 Very early TXA use in severely injured patients improves coagulopathy, decreases downstream blood product usage, and improves mortality.57,58 The time-dependent benefit has pushed TXA into prehospital formularies but also limits the population that qualifies for this therapy.59 As an antifibrinolytic, TXA is most useful in trauma-induced coagulopathy due to hyperfibrinolysis; the effectiveness of TXA in reversing FXa or VKA anticoagulation is less certain. There has been recent evidence that TXA may increase mortality if administered indiscriminately to all hemorrhaging patients.60 Waiting to administer TXA at the hospital where the presence of thrombolysis can be confirmed before administration of the drug may be prudent.

Blood product transfusion offers time-dependent mortality benefits, where even a 10-minute delay is associated with increased mortality.45 Because of the high-incidence of trauma-induced coagulopathy61 caused by hyperfibrinolysis,62 a “plasma-first” strategy is now being more widely used when plasma is available. Prehospital use of plasma improves short- and long-term survival.63

Increased availability of coagulation factor concentrates has created an attractive option for bleeding patients known to be on anticoagulant medications or with trauma-induced coagulopathy. European case reports have shown efficacy when administered before hospital arrival, with improved access to this therapy for patients served by rural hospitals.64,65 A single-center trial that compared the efficacy of first-line therapy using FFP versus coagulation factor concentrates for the reversal of trauma-induced coagulopathy was stopped early because the FFP group had significantly increased risk of rescue therapy and massive transfusion.66

Published experience and evidence of prehospital treatment of nontraumatic hemorrhage are sparse and primarily limited to case reports and single-institution experiences. Blood and plasma transfusion are used most often for critical GI bleeding, with improvements in hemodynamics and demonstrated reversal of coagulopathy.48–50 Mobile stroke units have been able to reverse anticoagulation before administration of tissue plasminogen activator67 or to treat ICH.47

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Barriers to Prehospital Hemorrhage Control

Several barriers prevent advancement in prehospital hemorrhage control options. Although the scope of practice varies among states, a prehospital provider’s education is the most limiting factor. Basic emergency medical technicians are primarily limited to the fundamental techniques of bandages and tourniquets. Paramedics, with roughly 1000 additional hours of initial training, can obtain vascular access and administer a wide variety of medications from a locally determined pharmacopeia. However, even today, large parts of the United States do not have access to paramedic-level care. Even where trained providers are available, operational barriers impact treatment options. Use of plasma may be evidence based, but the choice of plasma source, plasma preparation, and logistics including stock management requires consideration.68 Not all emergency vehicles have temperature-controlled storage for medications or blood products, and agencies distant from trauma centers may not have ready access to a blood bank. Freeze-dried or lyophilized plasma may extend access in the future but are not current options.

Recognition of external traumatic bleeding and some nontraumatic hemorrhage, such as GI hemorrhage, is straightforward and only requires a physical examination. Widespread availability of advanced diagnostics, such as ultrasound or mobile computed tomography, is not realistic, limiting detection of other types of life-threatening hemorrhage. Prehospital identification of patients taking anticoagulant medications, especially DOACs, is poor,52 and prehospital point-of-care testing of coagulation profiles is not widespread.

Presuming technological and educational advancements allow better prehospital recognition of hemorrhage in anticoagulated patients, the adoption rate of potential therapies will be driven by cost. Prehospital emergency medical care is primarily reimbursed at a fixed rate, with minor adjustments for patient acuity and geographic region. Care episodes that do not result in patient transportation are not reimbursed. Unlike hospitals, EMS agencies generally cannot itemize or separately bill for medications or procedures. Thus, effective treatments may not be economically feasible.

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EMERGENCY EVALUATION AND TREATMENT OF THE ANTICOAGULATED PATIENT WITH SEVERE BLEEDING

Emergency Medicine Perspective on the Trauma Patient

Injured patients who present to EDs and are taking oral anticoagulants account for 4% of all trauma patients. This subset of patients tends to be older, has more comorbidities, and has higher mortality than those not on anticoagulants. The structured approach to the evaluation of a traumatized patient who is taking an oral anticoagulant begins with the assessment of hemodynamic stability and the location of the hemorrhage.69,70 Control of the hemorrhage source using direct manual compression, tourniquet application, intravascular embolization, or surgical intervention should be attempted. Intravenous administration of vitamin K 5–10 mg should be given to those patients on VKAs. Supportive care with the administration of blood products, either whole blood or PRBCs, should proceed according to institutional policy and patient stability. Oral anticoagulants should clearly be stopped while a patient is being resuscitated, and consideration toward reversal and/or factor repletion should proceed in trauma patients with major or critical site hemorrhage. In mild or moderate bleeding, source control may be sufficient for hemostasis and obviates the need for factor replacement or reversal.

For patients taking VKAs who are compliant as evidenced by an elevated INR, 4FPCCs 25–50 U/kg should be given to replete key proteins in the coagulation cascade. FFP may be useful in factor repletion and plasma expansion in this scenario with careful attention to volume status and left ventricular function. For patients taking FXa inhibitors or dabigatran, the specific reversal agent should be administered if available. Other factors contributing to the decision to give specific reversal agents to a trauma patient with major bleeding are patient comorbidities. Uremia, chronic liver disease, thrombocytopenia, and the use of antiplatelet agents, including aspirin and PG2Y12 inhibitors such as clopidogrel and prasugrel, contribute to coagulopathy. In such cases, a more aggressive resuscitation and reversal strategy may include platelet administration, with the caveats mentioned previously. It is noteworthy to consider that treatment with factor replacement and reversal therapy carries significant expense, exposes the patient to their baseline or even increased risk of thromboembolism, and is not definitive therapy if the source of the hemorrhage is left unsecured.

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Intracranial Hemorrhage

TBI accounts for 2.5 million ED visits, 282,000 hospitalizations, and 56,000 deaths annually in the United States.71 The increased use of oral anticoagulants among older adults has led to an increased number of patients presenting to ED with suspected TBI.72 These patients may seem well and present with low mechanisms of injury, such as ground level falls, yet still have traumatic ICH that may require neurosurgical intervention.73,74 Efforts to develop clinical decision rules to identify a subpopulation of this group that is at low risk of injury, such that no neuroimaging is required, have met with limited success. Most patients with a suspected TBI who are taking anticoagulants should undergo neuroimaging.72 Delayed traumatic ICH, defined as blunt head injury with initially normal neuroimaging followed by interval development of ICH on repeat imaging, has been reported.75 The incidence of delayed traumatic ICH is unknown, although a recent retrospective review found that among patients taking DOACs who were at risk for traumatic ICH but had a negative brain computerized tomography (CT) on admission (n = 249), the incidence of delayed ICH was 0.8%.76 Evidence-based guidance to assist clinicians in establishing protocols for observation and repeat neuroimaging in TBI patients taking anticoagulants is limited.77,78 Some studies suggest that the subset of patients taking DOACs who have blunt traumatic ICH have lower mortality than those taking VKAs.79

ICHs, consisting of TBI, nontraumatic subarachnoid hemorrhages (SAHs), and spontaneous intracerebral hemorrhages, are neurologic emergencies that can lead to significant morbidity and mortality. Although these 3 broad categories of ICH are managed somewhat differently, almost all of them require immediate reversal of anticoagulation in addition to initial resuscitation that includes hemodynamic management, airway stabilization as needed, a neurologic examination, and a head CT. Patients who are on anticoagulants and sustain an ICH have a higher risk of death and hematoma expansion compared to those who are not anticoagulated, making anticoagulation reversal an important component of care for these patients. Rapid reversal of anticoagulation is usually necessary for even small, relatively asymptomatic hemorrhages to prevent hemorrhage expansion and to allow for completion of neurosurgical procedures or surgeries when indicated. Unlike patients with GI or retroperitoneal bleeding, those with isolated ICH do not require significant volume resuscitation, and even small increases in the amount of hemorrhage may lead to increased disability or mortality.

Prompt and aggressive anticoagulation reversal is important for long-term outcomes in patients with anticoagulant-related ICH. Time spent waiting on subspecialty consultation, transfer to another facility, or waiting on reversal after admission can impact long-term morbidity and mortality. A retrospective study of patients with intracerebral hemorrhage who were taking oral anticoagulants demonstrated that those who achieved a combination of INR reversal to <1.3 and systolic blood pressure reduction to <160 mm Hg within 4 hours had a significantly lower rate of hematoma enlargement (18.1% vs. 44.2%).80

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VKA-Associated ICH

Based on years of clinical practice and research, there are more data to support anticoagulation reversal practices in the setting of VKAs when compared with newer oral anticoagulants, particularly in the care of patients with ICH.81 Patients who experience an intracerebral hemorrhage while taking warfarin have a higher mortality than those who are not anticoagulated.82,83 The mainstays of reversal include FFP or PCCs combined with vitamin K. The 2015 American Heart Association guidelines for intracerebral hemorrhage state that “PCCs may have fewer complications and correct the INR more rapidly than FFP and might be considered over FFP (Class IIb, Level of Evidence B).”84 Based on available evidence, it is reasonable to assume that nearly all ICHs in the setting of VKA therapy represent a life threat and PCCs should be used for reversal. One criticism of PCC is that there has not been a large randomized controlled trial comparing it to FFP in the setting of ICHs. Smaller studies do support that PCCs reverse coagulopathy, defined as elevated INR, in patients with VKA-associated anticoagulation faster than FFP in the setting of both extracranial and intracranial bleeding.85

In a prospective observational study that compared treatment with PCCs and FFP in the setting of VKA-associated ICH, patients who received PCCs had a lower risk of death or severe disability at 3 months (P = 0.039) when compared with FFP alone. A randomized controlled trial comparing FFP to PCCs in the setting of VKA-associated ICH suggested that PCCs reversed INR faster than FFP;4 however, the trial was stopped early because of safety concerns due to greater hematoma expansion in the FFP group. Regardless of whether FFP or PCCs are used in the acute setting, patients also need to receive intravenous vitamin K to allow for the endogenous production of clotting factors.

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DOAC-Associated ICH

ICHs comprise only 13% of all major bleeds in all DOAC-treated patients.86 Of all DOAC bleeding complications, ICHs have the highest mortality at 45%.87 The risk of ICH is significantly lower in patients anticoagulated with a DOAC than with warfarin.18 In the RE-VERSE AD study, in which idarucizumab was evaluated for dabigatran reversal, 98 (32.3%) of the patients presented with ICH, including intracerebral hemorrhage, SAH, and subdural hematoma (SDH). The 30-day mortality rate was 16.4% among patients with ICH, which was lower than previously described rates of warfarin-associated ICH.30

The ANNEXA-4 full study report of andexanet alfa enrolled 171 patients (67% of total) with ICH.32 These constituted a mixture of intracerebral hemorrhage, SAH, and SDH, similar to the phase 3 idarucizumab study. The study population overall had a more favorable neurologic presentation at baseline, with an average presenting Glasgow Coma Scale (GCS) of 14. Patients with a GCS of <7 were excluded. Good or excellent hemostasis (as measured by the size of the hematoma) was achieved in 80% of patients.

For anticoagulated patients with ICH, several issues complicate the decision to treat with a specific reversal agent. First, the treating physician should strongly consider the goals of care. With the limited accuracy of ultra-early prognosis, patients with preinjury functional independence, even with major traumatic ICH, should be treated aggressively for the first 24–48 hours to try to preserve the opportunity for recovery. Similarly, an anticoagulated patient with a rim SDH and a GCS of 15 may be an excellent target for intervention to preserve their neurologic status. Contrary to historical practice, a decline in neurologic examination during serial examinations should not be the requirement for a decision to treat because clinical changes likely represent cerebral compression from progression of intracranial pathology. Although patients with GCS <7 were excluded from treatment in the ANNEXA trial, there is no clear reason to exclude patients with low GCS from treatment with andexanet alfa. Currently, there are no data on the natural progression of different types of ICH in patients taking DOACs, so risk stratification as a guide to decision-making is not reliable. Despite recommendations for early aggressive care, there are patients with a poor baseline quality of life with persistent neurologic deficits who may not receive meaningful benefit from intervention with a reversal agent. Finally, there are currently no data regarding redosing or extended infusion of andexanet alfa in patients with ICH; therefore, monitoring of TEG and repeating an anti-Xa level after initial dosing may be helpful, especially in patients with renal insufficiency.

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Abdominal and Chest Trauma

The evaluation and resuscitation of a patient with blunt thoracoabdominal trauma in the setting of anticoagulation are similar to that of a nonanticoagulated patient in that evaluation of the site and severity of hemorrhage are paramount. Initial concern that patients taking DOACs would have higher mortality than those taking VKAs in the setting of severe blunt traumatic injury, defined as an injury severity score >15, was not supported in recently published registry data. After excluding patients with severe head injuries, the authors found significantly lower mortality in the DOAC group versus the warfarin group (8.3% vs. 29.5%, respectively; P < 0.015). No difference in mean injury severity score, hospital or ICU length of stay, or complications was noted. Units of blood product transfused per patient were lower in the DOAC group (2.8 ± 1.8 units per patient in the DOAC group vs. 6.7 ± 6.4 units per patient in the warfarin group; P = 0.001).88 Initial imaging evaluation with Focused Assessment with Sonography in Trauma followed by cross-sectional imaging to identify the site and severity of bleeding is recommended. Repeat evaluation and observation as an inpatient or in a clinical decision or observation unit are prudent for patients for whom there is concern for bleeding in the setting of anticoagulation.

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GI Bleeding

In anticoagulated patients, GI bleeding is a common clinical problem that results in significant morbidity and cost. By some estimates, it accounts for up to 2% of hospital admissions with a mortality rate of 5%. Risk factors for DOAC-related GI bleeding include concomitant use of ulcerogenic agents (NSAIDs), older age, renal impairment, previous Helicobacter pylori infection, and history of GI bleed.89 Unlike warfarin, aspirin, and NSAIDs where UGIB predominates, LGIB accounted for 53% of GI bleeding with dabigatran. The most frequent sources of anticoagulant-associated GI bleeding are peptic ulcer disease for UGIB and colonic diverticula for LGIB.89

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Evaluation of GI Bleeding

Determination of the location of the GI bleed is important in patients who are anticoagulated in terms of how aggressively and urgently one must consider discontinuation of the anticoagulant and/or correction of the coagulopathic state, especially since LGIB stops spontaneously in 80%–85% of patients.90 Factors predictive of an upper GI source include a patient-reported history of melena, melanotic stools on examination, blood or coffee-ground emesis during nasogastric (NG) lavage, and blood urea nitrogen-to-serum Cr ratio >30. Up to 60% of patients with a history of UGIB are bleeding from the same lesion as a previous event91; therefore, history can help identify bleeding sources. Hematochezia suggests a lower GI source but can be seen in patients with massive UGIB or small bowel bleeding.

Whether all patients with suspected acute GI bleeding require NG tube placement and lavage remains controversial. Studies have failed to demonstrate a reduction in mortality, hospital length of stay, need for surgery, or transfusion requirement. However, NG tube lavage is associated with shorter time to GI endoscopy and assists in ruling out an upper GI source of bleeding. In anticoagulated patients, this additional information may be helpful in deciding whether reversal and push for urgent endoscopy are appropriate when UGIB is suspected.92

Frank red blood during NG lavage, tachycardia, orthostatic dizziness, cold/clammy extremities, and hemoglobin <8 g/dL suggest severe bleeding, as do confusion, angina, and palpitations. Serious hypovolemia is signaled by resting tachycardia (<15% blood volume loss), orthostatic hypotension (15%–40% volume loss), and supine hypotension (≥40% blood loss). Severe abdominal pain, rebound, and involuntary guarding raise one’s concern for perforation.

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Emergent Management

General emergency management includes triaging to an appropriate level of care, obtaining adequate intravenous access, and supportive measures. Nonmajor GI bleeding involves cessation of drug and delayed endoscopic management. If the bleeding is limited or slow, replacing lost fluid and blood products, if necessary, may be the best course of action while one waits for the anticoagulant effect to abate.12 Acute management of serious bleeding focuses on aggressive resuscitation, strategic drug reversal, and prompt endoscopy to control the bleeding source.93 Besides fluid and blood replacement, intermediate steps include the use of antifibrinolytic agents (TXA and desmopressin). The role of nonspecific reversal agents such as PCCs remains controversial. One study suggests that the use of PCC is associated with a 7% risk of thromboembolism.12

Patients with hypovolemia and active bleeding require red cell transfusion, even with an apparently normal hemoglobin at the onset. This is especially true if the patient remains hemodynamically unstable despite appropriate fluid resuscitation. Many guidelines recommend transfusion if hemoglobin falls below 9 g/dL; a more restrictive approach, however, using a hemoglobin of <7 g/dL has been shown to be safe with improved mortality. Given the risk of continued bleeding in anticoagulated individuals, a more robust transfusion threshold is appropriate.94 Equally important, one should avoid over transfusing patients with suspected variceal bleeding because this can precipitate worsening hemorrhage. Thrombocytopenia should be corrected when platelets fall below 50,000/μL. Because PRBCs do not contain coagulation factors, giving FFP for every 1–2 units of packed cells as part of a massive transfusion protocol is currently the standard of care for massively bleeding patients.89

With life-threatening bleeding in hemodynamically unstable patients, complete reversal is appropriate while seeking emergent endoscopy. Intervention with antifibrinolytic agents, nonspecific repletion agents (PCCs), and specific reversal agents such as idarucizumab and andexanet alfa is warranted. This occurs more often with UGIB since a large percentage of LGIB stops spontaneously.94

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Ancillary Therapeutic and Diagnostic Intervention

Acid suppression is paramount with UGIB. Proton pump inhibitors (PPIs) should be started at presentation. Whereas pre-endoscopy histamine receptor antagonists and acid suppressive therapy have not been shown to significantly lower the rate of ulcer rebleeding, high-dose antisecretory therapy with intravenous PPI infusion significantly reduces the rate of rebleeding compared to standard treatment in patients with bleeding ulcers. The PPIs also decrease length of stay, rebleeding rate, and need for blood transfusion postendoscopic intervention.95 Radiographic imaging such as CT scan, angiography, and radionuclide studies are sensitive but often less accurate for localizing the bleeding site. These studies are considered secondary to endoscopy, which has both diagnostic and therapeutic potential. Use of newer endoscopy techniques allows successful endoscopic management even in the setting of brisk bleeding.

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Mucosal Bleeding

Mucosal bleeding, such as epistaxis and postdental extraction, can be quite unnerving to the patient and frustrating for the physician, but rarely results in substantial morbidity or mortality. Bleeding can be more impressive, recurrent, and difficult to manage in patients with impaired hemostasis due to treatment with antiplatelet or anticoagulation medications.96 For mucosal bleeding, the risk-to-benefit ratio for systemic anticoagulation reversal or factor replenishment versus the underlying condition warranting anticoagulation would argue for local hemorrhage control as the first-line treatment. There is a limited base of quality evidence to inform management strategies.

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Epistaxis

Epistaxis can be characterized as anterior or posterior, with most nosebleeds originating from Kisselbach's plexus in the anterior nasal septum where they are easily controlled. Posterior nosebleeds, although infrequent, do have a greater likelihood of blood loss, difficulty in achieving hemostasis, and need for hospitalization and potential surgical intervention.

Direct pressure is the cornerstone of local bleeding control. For most nosebleeds, simply pinching and holding the nasal alae will, within a few minutes, prove sufficient for hemostasis. Failing that measure, nasal tampons allow for pressure to be directly applied against the offending vessel. Various devices are commonly available in the ED, including fluid-expandable sponge nasal tampons and inflatable nasal balloons. There has been no demonstrated advantage of one over the other although patient comfort has been reported to be improved with the inflatable nasal balloons.97 Posterior epistaxis can be controlled via nasal tampon deployment as well although a device of sufficient length is required. The classical solution to posterior epistaxis in the ED that is refractory to tampon placement is the use of a Foley style urinary balloon catheter, which is advanced in a similar fashion to a NG tube, inflated, and then pulled back into the nasal passages until lodging, which provides tamponade of the bleeding. Bilateral posterior packing may be required to achieve control. Despite this approach, bleeding may persist and surgical or interventional radiology consultation may be required for arterial ligation or embolization.

In addition to mechanical compression, there are pharmacologic adjuncts available in the form of topical vasoconstrictors or TXA. Commonly used topical vasoconstrictors include cocaine, phenylephrine, epinephrine, and oxymetazoline. TXA is a fibrin stabilizer that enhances hemostasis by blocking the activity of plasminogen.98 Recently, the use of topical TXA has been described in the setting of epistaxis using an atomizer, nebulizer, or saturating a nasal tampon with the injectable preparation (100 mg/mL solution).99–102 The use of chemical cautery allows for the obliteration of a bleeding vessel in the anterior septum, as long as the vessel can be visualized and the field is dry. Silver nitrate is typically used, with the caveat that it is applied only for a few seconds and not on both sides of the septum. In the anticoagulated patient, a prolonged period of observation before discharge from the ED may be warranted because the rebleed rate is higher in anticoagulated patients.96

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Oral Bleeding

The randomized controlled trial literature for oral bleeding (typically postdental extraction) in the ED is nonexistent at this time, with no available evidence in the anticoagulated patient cohort.103 The principles for controlling postextraction bleeding in the anticoagulated patient are similar to epistaxis—direct pressure remains critical. Rarely, arterial bleeding may require direct ligature with a figure-of-eight or purse-string stitch.

Hemostatic control of an extraction site can be accomplished by having the patient bite down on a small gauze roll after the preexisting clot and debris have been gently irrigated away. Direct pressure may be facilitated with local injection of lidocaine with epinephrine into the surrounding gingiva, both for vasoconstriction and pain relief from direct pressure onto a recent oral surgery site. Cohort data suggest an association with improved hemostasis when the gauze used for compression is saturated with TXA.104 Routine postoperative topical TXA mouthwash is associated with decreased oral bleeding in patients on VKAs such as warfarin; however, this regimen has not been prospectively studied in the setting of acute bleeding.105 Packing the socket with surgical gelatin foam may be an option for hemostasis, especially if TXA is not available.

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CRITICAL CARE MANAGEMENT OF THE ANTICOAGULATED PATIENT WITH SEVERE BLEEDING

Management of the Anticoagulated Patient in the Perioperative Setting

Patients who are severely injured rapidly develop a “coagulopathy of trauma” due to significant tissue damage.106 The current standard of care is to treat this coagulopathy by minimizing infusion of crystalloid and transfusing PRBCs and plasma (FFP) in a 1:1 ratio.107 Obtaining immediate hemorrhage control is critical to prevent the “lethal triad of trauma”: worsening coagulopathy, acidosis, and hypothermia. Hemorrhage control may involve use of tourniquets,108 aortic balloon occlusion,109 embolotherapy, or operative exploration. However, such a strategy does not address patients who have pharmacologic inhibition of the coagulation system in addition to the inherent coagulopathy of trauma. Such patients frequently require specific reversal agents to restore their innate clotting ability and decrease risk of fatal exsanguination related to the operation.

The PCCs have been shown to very rapidly and effectively reverse coagulopathy due to VKAs, most commonly warfarin, in patients who require emergency surgery.110,111 More recently, they have also been shown to improve time to correction of coagulopathy and to decrease the need for blood product transfusion when given in addition to a 1:1 transfusion strategy in hemorrhaging trauma patients.112 Although PCCs are costly, they are less likely than plasma to result in transfusion-associated circulatory overload and are associated with a lower overall transfusion need, both of which can offset the cost of the drug. Moreover, PCCs are now commonly available in most hospitals, making their use in the perioperative setting practical and feasible. However, PCCs should not be used alone for treatment of the exsanguinating patient because such patients require ongoing volume repletion, which is best carried out using plasma to replete ongoing consumption of coagulation factors and minimize the risk of hemodilution of these factors associated with crystalloid infusion.

Whereas treatment of bleeding patients who have coagulopathy due to the presence of warfarin is somewhat straightforward, management of severely injured bleeding patients who are taking DOACs is challenging. First, as previously mentioned, there is no readily available laboratory test that can measure for the presence or activity level of these agents in the serum. As such, the surgeon/intensivist must consider the severity of the bleed, time since the patient last ingested a dose of the drug, and the pharmacokinetics of the drug in the setting of the patient’s renal and liver function when determining whether or not to administer a reversal agent. Moreover, specific reversal agents for DOACs, especially andexanet alfa, are expensive. Waiting to evaluate whether the amount of hemorrhage is increasing may be a reasonable option in many instances, unless the patient presents in extremis where there is no physiologic reserve left or the patient has a significant hemorrhage in a closed space, such as the cranium. Also, the physician may be able to use secondary signs, such as the presence of blood clots on the stretcher or in the operative field, to determine coagulation status and inform the decision on use of DOAC-specific reversal agents. Ultimately, the surgeon must make a subjective assessment of the risk-to-benefit ratio regarding the patient’s likely anticoagulation status, the urgency of the surgery, and the ability to perform intraoperative reversal if necessary. Finally, the surgeon/intensivist should consider the duration of the reversal agent to determine the likelihood of rebound coagulopathy. Rebound coagulopathy may occur with andexanet alfa due to its short half-life and weak covalent bond to the FXa inhibitor, but it is much less likely to occur with idarucizumab, which irreversibly binds dabigatran.30

After operation, various endpoints should be used to determine coagulation ability. In addition to conventional coagulation parameters, TEG can be used to determine both clotting ability and clot stability (degree of fibrinolysis),113 but this modality is not predictive of the presence of DOACs. In addition to monitoring hemoglobin and lactic acid/base deficit levels, the amount and character of output from surgically placed drains can be used to assess for ongoing coagulopathy and possible need for (additional) doses of reversal agents.

The decision to resume anticoagulation postoperatively or after severe injury is challenging, and there are no set standards to follow. Delay to resumption of anticoagulation is associated with the risk of thromboembolic or occlusive disease whereas early resumption is associated with recurrent hemorrhage. Although one may be able to restart anticoagulation earlier in patients who have definitive control of hemorrhage, such as postsplenectomy, delay to resumption of anticoagulation may be necessary in patients in whom inherent clotting ability is needed for days to weeks to prevent worsening injury, such as with brain trauma.

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Evaluation and Treatment of Postprocedural Bleeding in the Anticoagulated Cardiac Patient

Anticoagulation During Cardiovascular Procedures

The introduction of a nonbiologic material or surface into the circulation represents a nidus for thrombus formation. This teleological response to “non-self” is the result of triggering the contact activation pathway, beginning with factor XIIa, factor XIa, prekallikrein, and high molecular weight kininogen. The insertion of catheters and stents and the performance of tissue ablation for the purpose of disrupting reentry circuits in AF and atrial flutter stimulate tissue factor–based coagulation.

The underlying mechanisms of thrombus formation, coupled with the risk for bleeding with anticoagulant therapy in an acute setting, have led to the development and wide-scale use of anticoagulants that have a rapid onset of action and short plasma half-life. The most commonly employed agent is unfractionated heparin (UFH); however, other parenteral anticoagulants such as bivalirudin, lepirudin, enoxaparin, and argatroban may also be used, particularly for percutaneous coronary intervention and in cases where UFH is contraindicated, such as in patients with heparin-induced thrombocytopenia.

DOACs, although increasingly used worldwide, are not a common first-line consideration in cardiovascular procedures; however, patients receiving DOACs who undergo pacemaker or internal cardioverter–defibrillator placement or direct-current cardioversion are increasingly kept on treatment. Accordingly, a keen understanding of these agents and their pharmacological profiles is an absolute requirement for clinicians in case bleeding complications occur.

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Bleeding Complications During Cardiovascular Procedures

Coronary angiography and percutaneous coronary intervention are among the most common diagnostic procedures and interventions, respectively, in patients with cardiovascular disease. The complications associated with coronary angiography are influenced by a variety of factors, including access site, sex, age, body weight, urgency of the procedure, and associated comorbidities. The most common complication is bleeding as a result of vascular trauma. This is particularly common among women of low body weight with small caliber peripheral vessels (femoral artery access site).114 In response to observed trends, there has been increasing use of the radial artery for access and use of ultrasound-guided arterial puncture (in the femoral and radial arteries).115 In the Minimizing Adverse hemorrhagic events by TransRadial access site and systemic Implementation of angioX (MATRIX) study, 8404 patients with acute coronary syndrome undergoing invasive management were randomly assigned to either radial or femoral access. The rates of major bleeding were significantly lower with the radial as compared with the femoral approach (relative risk, 0.58; 95% CI, 0.53–0.67).116

Close attention to the dosing of anticoagulants has also reduced the likelihood of periprocedural bleeding localized to the access site or the retroperitoneal space. Bleeding at a distance, including the GI tract, urinary tract, or central nervous system, is less common but certainly can occur. In addition, the coronary arteries themselves may bleed if perforation occurs. Although coronary arterial perforation is not a common event (0.2% of all cases), it causes cardiac tamponade in up to 30% of patients, a need for emergent surgery in 8%–10% of patients, and death in up to 8% of patients in whom it occurs.117

Hospitalized patients with cardiovascular disease may undergo a variety of procedures, including pacemaker or internal cardioverter–defibrillator placement, left ventricular assist device insertion, radiofrequency ablation, and peripheral arterial angioplasty, that can be associated with bleeding complications. As mentioned previously, UFH represents the most commonly used parenteral anticoagulant; however, DOACs are rapidly entering the picture because many electrophysiologists feel increasingly comfortable continuing these agents during procedures, at times with UFH given during the procedure to minimize the risk of thrombosis and thromboembolism. This approach will likely become more prevalent, and clinicians must take all anticoagulants and antithrombotic agents into consideration should serious bleeding ensue.

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Management of Bleeding Complications

The approach to managing bleeding complications in an anticoagulated patient should be stepwise, drug(s)-specific, and tailored to the site of bleeding and overall clinical status of the patient. An assessment of risk and benefit for stopping or reversing anticoagulation must be undertaken and, whenever possible, patient and family values and preferences must be factored into the equation. The initial treatment of anticoagulant-related bleeding is supportive with a focus on maintaining blood pressure and perfusion pressure, controlling the site of bleeding through either manual means when the site is readily accessible, vascular embolization or surgical intervention, blood product administration, and for serious, life-threatening or uncontrollable bleeding, replacement or reversal agents. Minor bleeding can often be addressed by employing supportive means or, in the case of access site bleeding, local measures including manual or device compression. Moderate bleeding may require monitoring in a step–down unit or its equivalent and catheter-based (embolization, cauterization, clipping) or minor surgical (vascular repair) intervention. Life-threatening bleeding events require immediate discontinuation of the anticoagulant, reversal of its anticoagulant effects, and specific interventions. UFH can be readily reversed with protamine following a standard institution-based protocol, which is recommended for all hospitals performing invasive cardiac procedures. There are potential complications associated with this agent that include myocardial suppression, hypotension, and paradoxical anticoagulation if overdosed and, rarely, anaphylactic shock. Supportive measures with volume expansion and PRBCs may also be required. Careful consideration of the potential impact of concomitant platelet antagonists and the possibility of transfusion of pooled platelets is essential. In patients receiving warfarin, 4FPCCs and vitamin K are recommended. If a patient is receiving a DOAC,118 a targeted approach that incorporates the use of specific reversal agents should be taken in addition to supportive care.

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Management of the Bleeding Patient in the Cardiovascular Critical Care Unit After Surgery/Cardiopulmonary Bypass and Extracorporeal Membrane Oxygenation

Bleeding in the cardiac surgical patient

In clinical practice, the management of bleeding patients in the cardiovascular critical care unit can be divided into those with medical bleeding and those with surgical bleeding. By far the most straightforward decision to treat is for those patients with surgical bleeding. When bleeding crosses certain accepted thresholds in the postoperative period, return to the OR for exploration and surgical control is mandatory. Massive bleeding has been defined differently at different times, but current use of the hemostasis score identifies massive bleeding as operative field blood loss exceeding 600 mL/h, chest tube output of >300 mL/h, or 150 mL/h for 2 hours. The Fresh Frozen Plasma in Cardiac Surgery: Descriptive and Prognostic Study (PLASMACARD) identified excessive postoperative bleeding as >1.5 mL/kg/h for ≥3 hours as requiring re-exploration in the OR.119

Bleeding vessels, pericardial bleeding, and valvular leakage must be fixed mechanically; however, control of postoperative “surgical bleeding” also relies on the correction of coagulopathy to allow for meticulous control of bleeding in the surgical field. Often patients are taken back to the OR for exploration for bleeding and no clear source is identified, but instead serosal oozing and leakage are noted. Controversy exists as to whether bleeding can be controlled via medical means, and multiple research studies have explored the use of antifibrinolytic therapies and procoagulants administered locally in the OR or systemically in an attempt to obviate the need to return to the OR.

The agents TXA, recombinant factor VIIa, protamine, FFP, and PCCs have all been studied in the perioperative setting. Recently, >3400 patients were included in a propensity-matched observational study investigating the effectiveness of PCCs versus FFP for coagulopathy treatment as first-line therapy in patients who were bleeding after cardiac surgery.120 Although the authors found a reduction in the need for red blood cell transfusion and a reduction in postoperative blood loss in patients treated with PCCs, there was a trend toward higher rates of acute kidney injury. It is unclear whether the use of PCCs increased the rates of postoperative thrombosis in these patients, but that possibility remains a critical risk to be explored in patients with vulnerable postoperative grafts and valves. Another key consideration is that PCCs are approved for the reversal of vitamin K–antagonized coagulopathy and the use in the postoperative patient is currently off-label unless specifically used to reverse the effects of warfarin taken before surgery.

The measurement of the extent of coagulopathy in these patients remains enigmatic as well. The use of point-of-care assays of coagulation, such as TEG and rotational thromboelastometry, remains variable even among large academic centers. It seems that the use of these phenotypic tests of clotting is increasing, yet the literature base and rigor needed to draw conclusions about the effectiveness of their inclusion in algorithmic approaches to the management of perioperative coagulopathy is lacking. To date, outcomes remain unstudied, the data focusing instead on the reduction of blood product transfusion as a result of the inclusion of TEG in management strategies. In one recent publication, the authors describe a single-center experience with the introduction of TEG into the postoperative management protocols and report an overall 40% reduction in the mean units of blood products used during overall hospitalizations for these patients.121 The reduction in usage of blood products seemed to return to pre-TEG levels in patients once they had progressed beyond 24 hours postoperatively.

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Bleeding After Cardiopulmonary Bypass

Cardiopulmonary bypass (CPB) requires that patients have large bore central arterial and venous cannulation performed to complete a CPB circuit and those cannulae require high-dose systemic anticoagulation to remain patent and to prevent thromboembolic events from impacting the circuit. Each of the components of the CPB circuit is generally heparin bonded with the exception of the oxygenator. Despite the heparin bonding, the CPB circuit is markedly thrombogenic through direct activation of the clotting cascade via contact-mediated coagulation and through a secondary pathway of inflammation. This inflammatory pathway also leads to a coagulopathy that closely resembles the consumptive pathology of disseminated intravascular coagulation. In addition to the consumption of thrombocytes by the CPB circuit, the priming of the circuit with crystalloid (the standard prime) creates a dilutional coagulopathy as does the use of cell-saver technologies which reintroduce collected red blood cells from the surgical field. This is done in the absence of the associated clotting factors found in serum. After CPB, there remains a coagulopathy from the use of intraoperative heparin despite heparin reversal with protamine at the end of the CPB run. Remnant heparin activity contributes to some element of postoperative bleeding in many cases. TEG, although gaining some following in the management of CPB patients, has also been reported to underdiagnose and fails to predict hypercoagulable states when present in these patients, and may not determine the underlying cause of bleeding in CPB patients. The cause of this phenomenon remains unclear, and further study is underway.122

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Bleeding in Patients on Extracorporeal Membrane Oxygenation

Bleeding while undergoing extracorporeal membrane oxygenation (ECMO) support is very common, with an estimated occurrence of over 40%. The most common site of bleeding in patients on venoarterial ECMO is the arterial cannula site, with an average transfusion volume of >10 units of PRBCs in most patients on circuit. Survival to discharge in patients on ECMO has been correlated with the total units of blood products required in numerous studies. Two variables that greatly affect the transfusion requirements are the efficiency of the ECMO circuit and the thresholds established by ECMO centers for blood product administration. There is no well-adopted clear threshold for ECMO patients’ transfusion targets, and most centers establish their own. Despite previous practice that established hemoglobin targets of 14 g/dL while on ECMO, including the current Extracorporeal Life Support Organization (ELSO) guidelines recommending hemoglobin levels of 12–14 g/dL, many modern ECMO teams are targeting lower hemoglobin thresholds. Long-term outcomes data are not available, but restrictive transfusion strategies in patients on venovenous ECMO have been described without reported increases in mortality. Nonetheless, lower hemoglobin targets lead to fewer transfusions.

The ECMO circuit efficiency is another key driver of rates of transfusion. Large cannulae, well-running centrifugal pumps, heparin-bonded circuits, and high-efficiency oxygenators all lead to less thrombosis and in-circuit consumption. Patients are systemically anticoagulated to prevent thrombosis using a therapeutic heparin PTT (hPTT) target of between 60 and 80 seconds in many units; lower-intensity heparinization at 40–60 seconds has also been used with similar effect in prevention of thrombosis and lower bleeding rates. Bleeding on ECMO circuits that is not easily controlled with surgical manipulation of cannulae is often catastrophic. When coagulopathy occurs due to factor consumption in the ECMO circuit, TEG and other standard measures of coagulation are used to guide reversal; however, the use of antifibrinolytics and prothrombotic agents is fraught with risk. Ultimately, coagulation of the circuit and clotting in the oxygenator lead to complement activation, consumptive coagulopathy, and hemolysis that is profoundly injurious to end-organ capillary beds, including the kidney and, more importantly, the brain. Therefore, the use of coagulopathy reversal agents while patients are on ECMO circuits is rare.

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Restarting Anticoagulant Therapy After Reversal to Prevent Thrombotic Complications

FXa inhibitors are widely used for the prevention of stroke in patients with AF. Patients with AF frequently undergo interventional procedures with attendant risks of bleeding, including catheter ablation of AF, pacemaker and defibrillator implantation, and left atrial appendage closure procedures. In the event of major life-threatening bleeding, FXa reversal may be pursued. When to again provide anticoagulation after reversal is a complicated clinical decision informed by the nature of the major bleeding event, the nature of the interventional procedure, and the underlying risk for thromboembolic events in the individual patient. Timely and optimal resumption of OAC are essential to minimize the risk of thromboembolic events.

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Electrophysiologic Procedures

There are many interventional electrophysiologic procedures, but in general, they can be grouped into 3 major categories for the purpose of this discussion. These categories include catheter-based procedures, such as diagnostic electrophysiology studies, catheter ablation of AF, and catheter ablation of ventricular tachycardia; device implantation procedures, such as pacemaker, defibrillator, and cardiac resynchronization procedures; and left atrial appendage occlusion procedures, such as Watchman device implantation. The bleeding risks of each of these procedures vary but include bleeding due to access site and vessel cannulation, intrathoracic bleeding such as cardiac perforation and tamponade, and bleeding at noninstrumented sites due to systemic anticoagulation, such as ICH. These procedures also carry an increased risk of thromboembolic events, particularly in the case of left-sided ablation procedures where instrumentation and prothrombotic changes in the chambers that lead directly to the arterial circulation increase the risk of stroke. For example, the risk of transient ischemic attack or stroke is approximately 1% in the 30 days after ablation.

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Use of Reversal Agents

The occurrence of major bleeding during or after electrophysiologic procedures in patients with therapeutic oral FXa inhibition requires cessation of DOAC therapy, provision of supportive measures, and correction of any anatomic sources of bleeding, such as femoral artery compression or pericardiocentesis. However, if bleeding continues or is life threatening, use of reversal agents may be necessary, alone or in conjunction with definitive surgical repair. As per a recent scientific statement from the American Heart Association, all healthcare institutions should have a perioperative bleeding management and DOAC reversal protocol.123

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Resumption of Anticoagulation

Administration of hemostatic factors can result in thromboembolism through a variety of mechanisms.124,125 Given the increased risks of thromboembolic events in patients with AF and the periprocedural risks of thromboembolic events, resuming OAC is an important priority after major bleeding, including life-threatening major bleeding. The risk of thromboembolic events was highlighted in the ANNEXA-4 trial, in which approximately 1 in 10 patients experienced a thrombotic event after administration of andexanet alfa for reversal of major, life-threatening bleeding. Similarly, at the conclusion of the major clinical trials that evaluated the use of DOACs compared with warfarin, transition off of FXa inhibitors was associated with an increased risk of stroke that correlated with prolonged time to therapeutic anticoagulation.126 The increased risks of thromboembolic events in these patient populations did not seem to be secondary to rebound phenomena. Rather, event rates increased with the duration of time off anticoagulation. Additionally, andexanet alfa may be prothrombotic due to increased thrombin generation, and this effect may contribute to some of the thrombotic events in patients who have received it.

Several conditions must be met before restarting anticoagulation can be considered. First, the major bleeding must have resolved. Second, the patient must be in an environment where reinitiating DOAC therapy and the patient’s response can be appropriately monitored. For most patients with life-threatening bleeding during or after an interventional electrophysiologic procedure, this will be in the hospital. The importance of appropriate supportive and interventional care cannot be overemphasized, and the benefit of resumption of anticoagulation must be balanced against the risk of complications. Supportive measures may include, but are not limited to, avoidance of unnecessary adjunctive antiplatelet therapy, appropriate surgical consultation and operative intervention when necessary, and transfusion of blood products when indicated.

The optimal approach to reinitiation of anticoagulation will depend upon each case; however, Figure 3 illustrates an approach to resumption of anticoagulation after an electrophysiologic procedure. Primary factors to consider include (1) the nature of the bleeding complication and anatomy; (2) the patient’s risk factors for thromboembolism (eg, Congestive heart failure-Hypertension-Age 2-Diabetes-Stroke/Transient ischemic attack 2-VAScular disease [CHA2DS2-VASc] score and other stroke risk factors); and (3) the specific procedure the patient underwent, such as device implantation versus left-sided ablation. For example, a patient with AF and no additional risk factors for stroke (CHA2DS2-VASc = 0) who experienced a spontaneous subarachnoid bleed after an elective pacemaker implant will be approached very differently than a patient with AF and a CHA2DS2-VASc score of 6 who had pericardial tamponade at the end of a catheter ablation procedure for AF. Patients with multiple risk factors for stroke and patients undergoing left-sided catheter ablation procedures are at the highest risk of postoperative thromboembolic events. For example, all patients undergoing catheter ablation of AF must receive therapeutic anticoagulation for 2–3 months after the procedure to reduce the risk of stroke.127

FIGURE 3

FIGURE 3

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Resumption of Anticoagulation After Cardiac Tamponade

A challenging and illustrative case in resumption of anticoagulation after major, life-threatening bleeding with reversal of FXa inhibition is the resumption of anticoagulation after cardiac tamponade. Patients who experience cardiac tamponade during catheter ablation require emergent pericardiocentesis. A pericardial drain is placed and drain output is carefully monitored after the procedure. If there is no significant evidence of repeat bleeding (minimal drain output), anticoagulation can be resumed. Ideally, this is done with administration of intravenous heparin without a bolus. If the patient tolerates therapeutic heparin without evidence of repeat bleeding, the pericardial drain is pulled and DOAC therapy is resumed. After 1–2 doses of DOAC therapy, an echocardiogram is usually repeated to ensure that there is no recurrence of the effusion.

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Resumption of Anticoagulation After ICH

Another challenging case is the resumption of OAC after the occurrence of ICH. Prophylactic subcutaneous enoxaparin may be started 24 hours after an ICH, provided ≥4 terminal half-lives of the anticoagulation agent used at the index time of the ICH have passed and a stability image shows no progression of bleeding. Registry data suggest that the majority of patients in clinical practice resume OAC after an ICH event within 6 months.128 In general, observational studies have shown that resuming OAC after prior ICH is associated with a 70% reduction in the risk of thromboembolism (relative risk, 0.31; 95% CI, 0.23–0.42).129 Systematic review and meta-analysis suggest that there is no evidence of increased risk of recurrent ICH after resuming OAC (relative risk, 1.01; 95% CI, 0.58–1.77), although the highest risk patients may not have resumed OAC.130 Of course, after an ICH event, everything should be done to minimize bleeding risk, including but not limited to optimal blood pressure control, avoidance of concomitant antiplatelet therapy whenever possible, and avoidance of other medications that increase bleeding risk, such as NSAIDs. When to resume OAC after an ICH event is a controversial decision that, again, depends on the specific circumstances of the bleeding event, the risk factors for recurrent ICH, and the patient’s underlying risk for thromboembolism. Care must be used in patients with primary ICH, and a risk/benefit analysis much be performed for each patient. For example, a patient with cerebral amyloid angiopathy would likely be too high risk to be anticoagulated, but a patient without underlying vascular abnormalities and a hypertensive etiology of hemorrhage may be appropriate for anticoagulation after hypertension has been controlled. Resumption of therapeutic anticoagulation usually occurs 2–4 weeks after the bleeding event.131

Further studies are needed to clarify optimal strategies for resumption of OAC after an ICH event. Fortunately, there are several ongoing clinical trials that will help clarify best practices. For example, the Apixaban versus Antiplatelet drugs or no antithrombotic drugs after anticoagulation-associated intraCerebral HaEmorrhage in patients with Atrial Fibrillation (APACHE-AF) trial will enroll patients with AF and recent ICH and randomize them to apixaban versus avoidance of OAC.132

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CONCLUSIONS AND FUTURE DIRECTIONS

The use of oral anticoagulants is becoming more common as the population ages, and anticoagulant-related bleeding events will continue to increase in frequency. This monograph summarizes the recommendations of the EMCREG-International Multidisciplinary Severe Bleeding Consensus Panel regarding management of severe bleeding in patients on oral anticoagulants based on currently available data. There are many areas, however, where further research is required. Most importantly, current data on the efficacy of DOAC reversal agents are based on improvement in bleeding times; there has been no randomized controlled trial to evaluate the efficacy of reversal agents based on patient outcomes. Additionally, an analysis of the pharmacoeconomics of reversal agents is necessary to evaluate the cost of the drug as it relates to the cost of the episode of care and quality-adjusted life years. Because of the short half-life of andexanet alfa, repeat dosing may be necessary, but the strategies for repeat dosing and the measures used to drive repeat dosing have yet to be clearly defined. A time-to-treat analysis to determine the therapeutic window during which reversal agents can be used would be beneficial as well, especially for physicians who will be making the decision to transfer patients with life-threatening bleeds to institutions that have reversal agents available. The role of renal insufficiency in treatment with reversal agents, particularly as it relates to the treatment window, remains to be defined. The role of 4FPCCs in patients with DOAC-related bleeding must be evaluated as well. There are currently no studies linking clinical outcomes to the use of 4FPCCs in bleeding patients, and the upstream use of 4FPCCs may preclude use of andexanet alfa because of the risk of severe complications. And finally, it is imperative that the optimal timing for resumption of anticoagulation to avoid thrombotic complications be investigated.

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      Keywords:

      4-factor prothrombin complex concentrates; andexanet alfa; anticoagulation; bleeding reversal; coumadin; factor IIa inhibitors; factor Xa inhibitors; idarucizumab; severe bleeding

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