High-Risk Cardiovascular Emergencies - DOACs
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Course 2: Management of Patients Taking Direct Oral Anticoagulant Agents

The use of direct oral anticoagulants – the direct thrombin inhibitor and the anti-factor Xa inhibitors – has increased greatly since 2010, when the first agent was approved by the FDA. Though DOACs are popular with patients because they don’t require the lab monitoring and dietary changes of warfarin, these patients can present new challenges to emergency clinicians.

What are the pharmacokinetics of the different DOAC agents?

What is the half-life of each drug and how does this figure into ED management of a patient who needs emergent surgical intervention?

Is the threshold for ordering neuroimaging the same for DOACs as it is for warfarin?

What is the best lab test for measuring hemostasis for the direct thrombin inhibitor? Anti-factor Xa inhibitors? Why?

Which DOACs have specific reversal agents?

Which scoring system is best for assessing bleeding risk? HAS-BLED, ORBIT, ABC?

Hemodialysis, PCC, rFVIIa, fresh-frozen plasma, tranexamic acid, vitamin K, activated charcoal: what works and what doesn’t?

Is a patient on a DOAC eligible for intravenous thrombolysis?

When should a DOAC be started in the ED?

What are the cautions regarding renal dosing for DOACs?

Table of Contents
  1. Abstract
  2. Case Presentations
  3. Introduction
  4. Critical Appraisal of the Literature
  5. Pathophysiology
  6. Mechanisms and Comparison of Direct Oral Anticoagulants
    1. Direct Thrombin Inhibitor
    2. Factor Xa Inhibitors
      1. Rivaroxaban
      2. Apixaban
      3. Edoxaban
      4. Betrixaban
  7. Prehospital Care
  8. Emergency Department Evaluation
  9. Diagnostic Studies
    1. Imaging Studies
      1. Computed Tomography
      2. Ultrasound
    2. Laboratory Studies
      1. General Testing
      2. Prothrombin Time/ International Normalized Ratio and Partial Thromboplastin Time
      3. Anti-Factor Xa Activity Levels
      4. Thrombin Time
      5. Ecarin Clotting Time
  10. Treatment
    1. General Principles
    2. Specific Reversal Agents
      1. Idarucizumab
      2. Coagulation Factor Xa (Recombinant), Inactivated-zhzo (Andexanet Alfa)
    3. Nonspecific Reversal Agents
      1. Prothrombin Complex Concentrate
      2. Activated PCC (Factor VIII Inhibitor Bypassing Activity)
      3. Recombinant Factor VIIa (rFVIIa)
      4. Fresh-Frozen Plasma
    4. Adjunct Therapies
      1. Activated Charcoal for Oral Agents
      2. Tranexamic Acid
      3. Vitamin K
      4. Hematology Consultation/Transfer
  11. Special Circumstances/Populations
    1. Patients With Valvular Disease
    2. Pregnant, Breastfeeding, and Pediatric Patients
    3. Patients With Renal Impairment
  12. Controversies and Cutting Edge
    1. Treatment of Ischemic Stroke in Patients Taking Direct Oral Anticoagulants
    2. Scoring Systems for Bleeding Risk
    3. Hemodialysis for Dabigatran Removal
    4. Viscoelastic Testing
    5. Ciraparantag
  13. Disposition
    1. Patients Currently Taking Direct Oral Anticoagulants
    2. Emergency Department Initiation of Direct Oral Anticoagulants
  14. Summary
  15. Risk Management Pitfalls for Patients Taking Direct Oral Anticoagulant Agents
  16. Time- And Cost-Effective Strategies
  17. Case Conclusions
  18. Clinical Pathway for Management of Hemorrhage in Patients Taking Direct Oral Anticoagulant Agents
  19. Tables and Figures
    1. Table 1. Comparison of Pharmacokinetics/Pharmacodynamics of Direct Oral Anticoagulant Agents
    2. Table 2. Key Elements From the History and Physical Examination of Patients on Direct Oral Anticoagulant Agents
    3. Table 3. Scoring Systems for Bleeding Risk
    4. Figure 1. Clotting Factor Cascade and Site of Action of Oral Anticoagulant Agents
  20. References

Abstract

Direct oral anticoagulant (DOAC) agents have become commonly used over the last 9 years for treatment and prophylaxis for thromboembolic conditions, following approvals by the United States Food and Drug Administration. These anticoagulant agents, which include a direct thrombin inhibitor and factor Xa inhibitors, offer potential advantages for patients over warfarin; however, bleeding emergencies with DOACs can present diagnostic and therapeutic challenges because, unlike traditional anticoagulants, their therapeutic effect cannot be easily monitored directly with common clotting assays. This review examines the growing body of evidence on the uses and risks of DOACs in the emergency department, including initiation of therapy and reversal strategies.

 

Case Presentations

As you begin your shift, the first patient is a 70-year-old man brought in for a ground-level fall with isolated head injury. A review of the patient’s history reveals atrial fibrillation, and he is currently on anticoagulation with apixaban. A rapidly obtained CT scan of the head shows a subdural hematoma. As you resuscitate the patient, you wonder how best to assess his anticoagulation status and how best to address reversal.

Later in the shift, a 50-year-old woman is brought in by EMS for intentional overdose of medications, in a suicide attempt. Her list of home medications includes sedatives as well as dabigatran, prescribed for a recently diagnosed DVT. The patient is somnolent, so specific ingestants cannot be ascertained. You wonder if there are monitoring tests, beyond PT/PTT, that might determine whether a dabigatran overdose is present, and if so, how should it be managed to prevent further injury?

As your shift is coming to a close, a 45-year-old man presents with leg swelling and erythema after a recent airplane trip. Your bedside ultrasound is consistent with DVT. The patient hates the thought of frequent blood tests, and he asks whether there are any options for treatment besides warfarin. You know that DOACs may be an option for him, but you wonder what the best way is to engage in shared decision-making with him.

 

Introduction

Since the approval by the United States Food and Drug Administration (FDA) of dabigatran in 2010, the prescription market for this new class of medications with direct anticoagulation effect has increased markedly. In the United States, DOACs now account for a similar proportion of office visits for anticoagulant use as warfarin. This trend has also been seen in other countries, as DOAC use has grown rapidly.1-3 Assuming that this trend continues, emergency clinicians will continue to see more patients taking DOACs, as these drugs replace alternative anticoagulant therapies.

Compared with warfarin and other oral anticoagulants, DOACs offer potential benefits, including reduced need for monitoring and a potential for reduced bleeding complications. However, the advisability of using the DOACs was initially challenged, due to the lack of an effective reversal agent to use in the event of an emergency and for the risk of unintentional overdose in patients with altered drug metabolism. As with traditional anticoagulants, patients using DOACs are often medically complex, and they may frequently present for emergency department (ED) care.

This issue of Emergency Medicine Practice focuses on updates to the body of literature on DOACs since the last review in 2013. Since that time, many studies, including longer-term follow-up from large trials and registry data for patients taking DOACs, have become available. Given the likelihood that these medications will continue to increase in popularity, emergency clinicians need to have expertise in dosing, monitoring, reversal, and risks in clinical practice. This review will focus on use of DOACs for the indications of stroke prevention in atrial fibrillation and treatment and prevention of recurrence in venous thromboembolism (VTE).

 

Critical Appraisal of the Literature

Terminology for this class of anticoagulants has included, most commonly, DOAC (for direct oral anticoagulant) or NOAC (for “novel” oral anticoagulant or “non–vitamin K” oral anticoagulant).4 Given their direct mechanism of action, and the time since approval for these agents, DOAC may be the preferred term in the future.

A literature search was performed in PubMed using the following terms: DOAC, NOAC, dabigatran, apixaban, edoxaban, rivaroxaban, betrixaban, pulmonary embolism, deep venous thrombosis, and prothrombin complex concentrate. Over 200 articles from 2000 to the present were reviewed. The Cochrane Database of Systematic Reviews was searched for systematic reviews using the key term DOAC, which identified 5 reviews. Guideline statements specifically regarding DOAC treatment and reversal were released by the American Heart Association (AHA) in 2017, the European Society of Cardiology in 2015, and the American College of Cardiology in 2017. These guidelines include data based on large randomized controlled trials for multiple conditions.

An appraisal of literature was performed, which favored large randomized trials over smaller cohort studies and case reports. Good-quality evidence regarding safety and efficacy of these medications in comparison to warfarin and heparin-based anticoagulants has been published based on long-term cohort studies. Unfortunately, direct comparisons between DOACs are limited to small numbers of studies with predominantly poor-quality evidence. Differences in inclusion and exclusion criteria, primary endpoints, and assessment of safety outcomes between studies also limits comparability between trials. When available, recommendations in this article are evidence-based. Recommendations based on accepted practice or expert consensus are explicitly noted as such.

 

Risk Management Pitfalls for Patients Taking Direct Oral Anticoagulant Agents

1. “The patient denied taking warfarin or enoxaparin for his DVT, but we didn’t ask about other anticoagulants.“

DOACs are now being prescribed frequently, and patients should be questioned specifically about these medications if they have a condition that indicates they might be using them.

5. “The INR was below 2.0, so I didn’t think the anticoagulation effect was present.”

Standard coagulation testing is insensitive for evaluating DOAC anticoagulant effect, and even normal results can be present, despite therapeutic levels of medication.

9. “I didn’t think the patient would be at risk of clotting after DOAC reversal.”

Reversing DOACs can put patients at higher risk of new thrombosis, and discussion of the risks and benefits of reversal should be documented, if possible.

 

Tables and Figures

Table 1. Comparison of Pharmacokinetics / Pharmacodynamics of Direct Oral Anticoagulant Agents

 

References

Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.

To help the reader judge the strength of each reference, pertinent information about the study, such as the type of study and the number of patients in the study is included in bold type following the references, where available. In addition, the most informative references cited in this paper, as determined by the author, are highlighted.

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