Emergency Department Management of Patients Taking Direct Oral Anticoagulant Agents

Table of Contents

 

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?

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

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.

1. Alalwan AA, Voils SA, Hartzema AG. Trends in utilization of warfarin and direct oral anticoagulants in older adult patients with atrial fibrillation. Am J Health Syst Pharm. 2017;74(16):1237-1244. (Cross-sectional longitudinal analysis)
2. Barnes GD, Lucas E, Alexander GC, et al. National trends in ambulatory oral anticoagulant use. Am J Med. 2015;128(12):1300-1305. (Review of national outpatient database)
3. van den Heuvel JM, Hovels AM, Buller HR, et al. NOACs replace VKA as preferred oral anticoagulant among new patients: a drug utilization study in 560 pharmacies in the Netherlands. Thromb J. 2018;16:7. (Prescription review of 247,927 patients)
4. Barnes GD, Ageno W, Ansell J, et al. Recommendation on the nomenclature for oral anticoagulants: communication from the SSC of the ISTH. J Thromb Haemost. 2015;13(6):1154-1156. (Recommendation statements)
5. Hirsh J, Fuster V, Ansell J, et al. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. Circulation. 2003;107(12):1692-1711. (Guidelines)
6. Chan NC, Eikelboom JW, Weitz JI. Evolving treatments for arterial and venous thrombosis: role of the direct oral anticoagulants. Circ Res. 2016;118(9):1409-1424. (Review)
7. Li A, Garcia DA, Lyman GH, et al. Direct oral anticoagulant (DOAC) versus low-molecular-weight heparin (LMWH) for treatment of cancer associated thrombosis (CAT): a systematic review and meta-analysis. Thromb Res. 2019;173:158-163. (Meta-analysis; 15 articles, 2 randomized controlled trials)
8. Montiel FS, Ghazvinian R, Gottsäter A, et al. Treatment with direct oral anticoagulants in patients with upper extremity deep vein thrombosis. Thromb J. 2017;15:26. (Registry analysis; 83 patients)
9. Nery F, Valadares D, Morais S, et al. Efficacy and safety of direct-acting oral anticoagulants use in acute portal vein thrombosis unrelated to cirrhosis. Gastroenterol Res. 2017;10(2):141-143. (Case report; 1 patient)
10. Andreas M, Moayedifar R, Wieselthaler G, et al. Increased thromboembolic events with dabigatran compared with vitamin K antagonism in left ventricular assist device patients: a randomized controlled pilot trial. Circ Heart Fail. 2017;10(5). (Randomized controlled trial; 30 patients)
11. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-1151. (Randomized controlled trial; 18,113 patients)
12. Connolly SJ, Wallentin L, Ezekowitz MD, et al. The long-term multicenter observational study of dabigatran treatment in patients with atrial fibrillation (RELY-ABLE) study. Circulation. 2013;128(3):237-243. (Randomized controlled trial; 5851 patients)
13. Hart RG, Diener H-C, Yang S, et al. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial. Stroke. 2012;43(6):1511-1517. (Randomized controlled trial; 18,113 patients)
14. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342-2352. (Randomized controlled trial; 2539 patients)
15. Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129(7):764-772. (Randomized controlled trial; 2589 patients)
16. Schulman S, Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368(8):709-718. (Randomized controlled trial; 2856 patients)
17. Sherwood MW, Douketis JD, Patel MR, et al. Outcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: results from the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF). Circulation. 2014;129(18):1850-1859. (Randomized controlled trial; 14,286 patients)
18. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891. (Randomized controlled trial; 14,264 patients)
19. Sherwood MW, Nessel CC, Hellkamp AS, et al. Gastrointestinal bleeding in patients with atrial fibrillation treated with rivaroxaban or warfarin: ROCKET AF trial. J Am Coll Cardiol. 2015;66(21):2271-2281. (Randomized controlled trial; 14,286 patients)
20. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-2510. (Randomized controlled trial; 3449 patients)
21. EINSTEIN-PE Investigators, Büller HR, Prins MH, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287-1297. (Randomized controlled trial; 4832 patients)
22. Weitz JI, Lensing AWA, Prins MH, et al. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med. 2017;376(13):1211-1222. (Randomized controlled trial; 3396 patients)
23. Young AM, Marshall A, Thirlwall J, et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018;36(20):2017-2023. (Randomized controlled trial; 203 patients)
24. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-992. (Randomized controlled trial; 18,201 patients)
25. Hylek EM, Held C, Alexander JH, et al. Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin: the ARISTOTLE trial (apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation): predictors, characteristics, and clinical outcomes. J Am Coll Cardiol. 2014;63(20):2141-2147. (Randomized controlled trial; 18,140 patients)
26. Bahit MC, Lopes RD, Wojdyla DM, et al. Non-major bleeding with apixaban versus warfarin in patients with atrial fibrillation. Heart. 2017;103(8):623-628. (Randomized controlled trial; 18,140 patients)
27. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799-808. (Randomized controlled trial; 5395 patients)
28. Jaspers Focks J, Brouwer MA, Wojdyla DM, et al. Polypharmacy and effects of apixaban versus warfarin in patients with atrial fibrillation: post hoc analysis of the ARISTOTLE trial. BMJ. 2016;353:i2868. (Randomized controlled trial; 18,140 patients)
29. Alexander JH, Lopes RD, James S, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med. 2011;365(8):699-708. (Randomized controlled trial; 7392 patients)
30. Goldhaber SZ, Leizorovicz A, Kakkar AK, et al. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med. 2011;365(23):2167-2177. (Randomized controlled trial; 6528 patients)
31. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093-2104. (Randomized controlled trial; 21,105 patients)
32. Hokusai VTEI, Büller HR, Décousus H, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406-1415. (Randomized controlled trial; 4921 patients)
33. Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018;378(7):615-624. (Open-label randomized controlled trial; 1050 patients)
34. Cohen AT, Harrington RA, Goldhaber SZ, et al. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016;375(6):534-544. (Randomized controlled trial; 7513 patients)
35. Gibson CM, Chi G, Halaby R, et al. Extended-duration betrixaban reduces the risk of stroke versus standard-dose enoxaparin among hospitalized medically ill patients: an APEX trial substudy (Acute medically ill venous thromboembolism Prevention with Extended duration betrixaban). Circulation. 2017;135(7):648-655. (Randomized controlled trial; 7513 patients)
36. Nishijima DK, Gaona S, Waechter T, et al. Do EMS providers accurately ascertain anticoagulant and antiplatelet use in older adults with head trauma? Prehosp Emerg Care. 2017;21(2):209-215. (Retrospective cohort; 2110 patients)
37. Berger R, Salhanick SD, Chase M, et al. Hemorrhagic complications in emergency department patients who are receiving dabigatran compared with warfarin. Ann Emerg Med. 2013;61(4):475-479. (Prospective observational study; 138 patients)
38. Nishijima DK, Offerman SR, Ballard DW, et al. Risk of traumatic intracranial hemorrhage in patients with head injury and preinjury warfarin or clopidogrel use. Acad Emerg Med. 2013;20(2):140-145. (Prospective cohort; 982 patients)
39. Shah KH, Newman DH, Raja AS. Repeated CTs-let’s use our heads. Ann Emerg Med. 2012;60(4):537-538; author reply 538. (Letter)
40. Menditto VG, Lucci M, Polonara S, et al. Management of minor head injury in patients receiving oral anticoagulant therapy: a prospective study of a 24-hour observation protocol. Ann Emerg Med. 2012;59(6):451-455. (Prospective case series; 97 patients)
41. Li J. Admit all anticoagulated head-injured patients? A million dollars versus your dime. You make the call. Ann Emerg Med. 2012;59(6):457-459. (Editorial)
42. Nishijima DK, Offerman SR, Ballard DW, et al. Immediate and delayed traumatic intracranial hemorrhage in patients with head trauma and preinjury warfarin or clopidogrel use. Ann Emerg Med. 2012;59(6):460-468. (Prospective cohort; 1064 patients)
43. Bauman ZM, Ruggero JM, Squindo S, et al. Repeat head CT? Not necessary for patients with a negative initial head CT on anticoagulation or antiplatelet therapy suffering low-altitude falls. Am Surg. 2017;83(5):429-435. (Prospective observational analysis; 1180 patients)
44. Feeney JM, Santone E, DiFiori M, et al. Compared to warfarin, direct oral anticoagulants are associated with lower mortality in patients with blunt traumatic intracranial hemorrhage: a TQIP study. J Trauma Acute Care Surg. 2016;81(5):843-848. (Registry retrospective analysis)
45. Jagoda AS, Bazarian JJ, Bruns JJ, et al. Clinical policy: neuroimaging and decisionmaking in adult mild traumatic brain injury in the acute setting. Ann Emerg Med. 2008;52(6):714-748. (Clinical policy)
46. Hoff WS, Holevar M, Nagy KK, et al. Practice management guidelines for the evaluation of blunt abdominal trauma: the East Practice Management Guidelines Work Group. J Trauma. 2002;53(3):602-615. (Guidelines statement)
47. Sunga KL, Bellolio MF, Gilmore RM, et al. Spontaneous retroperitoneal hematoma: etiology, characteristics, management, and outcome. J Emerg Med. 2012;43(2):e157-e161. (Prospective cohort; 346 patients)
48. Feeney JM, Neulander M, DiFiori M, et al. Direct oral anticoagulants compared with warfarin in patients with severe blunt trauma. Injury. 2017;48(1):47-50. (Retrospective trauma registry analysis)
49. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315-352. (Guidelines statement)
50. Kutcher ME, Redick BJ, McCreery RC, et al. Characterization of platelet dysfunction after trauma. J Trauma Acute Care Surg. 2012;73(1):13-19. (Prospective study; 101 patients)
51. Frontera JA, Lewin JJ 3rd, Rabinstein AA, et al. Guideline for reversal of antithrombotics in intracranial hemorrhage: executive summary. A statement for healthcare professionals from the Neurocritical Care Society and the Society of Critical Care Medicine. Crit Care Med. 2016;44(12):2251-2257. (Guideline)
52. Reilly PA, Lehr T, Haertter S, et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol. 2014;63(4):321-328. (Retrospective analysis; 9183 patients)
53. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124(14):1573-1579. (Randomized controlled trial; 12 volunteers)
54. Testa S, Legnani C, Tripodi A, et al. Poor comparability of coagulation screening test with specific measurement in patients receiving direct oral anticoagulants: results from a multicenter/multiplatform study. J Thromb Haemost. 2016;14(11):2194-2201. (In vitro study)
55. Samuelson BT, Cuker A, Siegal DM, et al. Laboratory assessment of the anticoagulant activity of direct oral anticoagulants: a systematic review. Chest. 2017;151(1):127-138. (Review)
56. Steiner T, Böhm M, Dichgans M, et al. Recommendations for the emergency management of complications associated with the new direct oral anticoagulants (DOACs), apixaban, dabigatran and rivaroxaban. Clin Res Cardiol. 2013;102(6):399-412. (Review)
57. Cuker A, Siegal DM, Crowther MA, et al. Laboratory measurement of the anticoagulant activity of the non–vitamin K oral anticoagulants. J Am Coll Cardiol. 2014;64(11):1128-1139. (Review)
58. Becker RC, Yang H, Barrett Y, et al. Chromogenic laboratory assays to measure the factor Xa-inhibiting properties of apixaban--an oral, direct and selective factor Xa inhibitor. J Thromb Thrombolysis. 2011;32(2):183-187. (In vitro study)
59. Stengel D, Ottersbach C, Matthes G, et al. Accuracy of single-pass whole-body computed tomography for detection of injuries in patients with major blunt trauma. CMAJ. 2012;184(8):869-876. (Retrospective cohort; 1756 patients)
60. Samama MM, Contant G, Spiro TE, et al. Evaluation of the anti-factor Xa chromogenic assay for the measurement of rivaroxaban plasma concentrations using calibrators and controls. Thromb Haemost. 2012;107(2):379-387. (In vitro study)
61. Samama MM, Martinoli J-L, LeFlem L, et al. Assessment of laboratory assays to measure rivaroxaban--an oral, direct factor Xa inhibitor. Thromb Haemost. 2010;103(4):815-825. (In vitro study)
62. Ruff CT, Giugliano RP, Braunwald E, et al. Association between edoxaban dose, concentration, anti-factor Xa activity, and outcomes: an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet. 2015;385(9984):2288-2295. (Randomized controlled trial; 21,105 patients)
63. Stangier J, Clemens A. Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor. Clin Appl Thromb Hemost. 2009;15 Suppl 1:9S-16S. (In vitro study; healthy volunteers)
64. Nowak G. The ecarin clotting time, a universal method to quantify direct thrombin inhibitors. Pathophysiol Haemost Thromb. 2003;33(4):173-183. (Review)
65. Tomaselli GF, Mahaffey KW, Cuker A, et al. 2017 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American College Of Cardiology task force on expert consensus decision pathways. J Am Coll Cardiol. 2017;70(24):3042-3067. (Guidelines statement)
66. Brown MA, Daya MR, Worley JA. Experience with chitosan dressings in a civilian EMS system. J Emerg Med. 2009;37(1):1-7. (Case series; 34 patients)
67. QuikClot^® - FAQs–learn more about our hemostatic devices. http://quikclot.com/FAQ. (Website)
68. Carson JL, Hill S, Carless P, et al. Transfusion triggers: a systematic review of the literature. Transfus Med Rev. 2002;16(3):187-199. (Review)
69. Carson JL, Guyatt G, Heddle NM, et al. Clinical practice guidelines from the AABB: red blood cell transfusion thresholds and storage. JAMA. 2016;316(19):2025-2035. (Guidelines statement)
70. Carson JL, Triulzi DJ, Ness PM. Indications for and adverse effects of red-cell transfusion. N Engl J Med. 2017;377(13):1261-1272. (Review)
71. Mazer CD, Whitlock RP, Fergusson DA, et al. Restrictive or liberal red-cell transfusion for cardiac surgery. N Engl J Med. 2017;377(22):2133-2144. (Randomized controlled trial; 5243 patients)
72. Kim JH, Baek CH, Min JY, et al. Desmopressin improves platelet function in uremic patients taking antiplatelet agents who require emergent invasive procedures. Ann Hematol. 2015;94(9):1457-1461. (Prospective study; 23 patients)
73. Kaufman RM, Djulbegovic B, Gernsheimer T, et al. Platelet transfusion: a clinical practice guideline from the AABB. Ann Intern Med. 2015;162(3):205-213. (Guidelines statement)
74. Spiller HA, Mowry JB, Aleguas A, et al. An observational study of the factor Xa inhibitors rivaroxaban and apixaban as reported to eight poison centers. Ann Emerg Med. 2016;67(2):189-195. (Prospective cohort; 138 patients)
75. Conway SE, Schaeffer SE, Harrison DL. Evaluation of dabigatran exposures reported to Poison Control centers. Ann Pharmacother. 2014;48(3):354-360. (Retrospective review; 806 cases)
76. Pollack CV, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373(6):511-520. (Prospective cohort; 90 patients)
77. Pollack CV, Reilly PA, van Ryn J, et al. Idarucizumab for dabigatran reversal - full cohort analysis. N Engl J Med. 2017;377(5):431-441. (Prospective cohort; 503 patients)
78. Burnett AE, Mahan CE, Vazquez SR, et al. Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment. J Thromb Thrombolysis. 2016;41:206-232. (Guidelines statement)
79. Alikhan R, Rayment R, Keeling D, et al. The acute management of haemorrhage, surgery and overdose in patients receiving dabigatran. Emerg Med J. 2014;31(2):163-168. (Review)
80. Raval AN, Cigarroa JE, Chung MK, et al. Management of patients on non-vitamin K antagonist oral anticoagulants in the acute care and periprocedural setting: a scientific statement from the American Heart Association. Circulation. 2017;135(10):e604-e633. (Guidelines statement)
81. Connolly SJ, Crowther M, Eikelboom JW, et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med. 2019;380(14):1326-1335. (Prospective cohort; 352 patients)
82. Connolly SJ, Milling TJ, Eikelboom JW, et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016;375(12):1131-1141. (Prospective cohort; 47 patients)
83. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373(25):2413-2424. (Randomized controlled trial; 24 patients)
84. Fredriksson K, Norrving B, Strömblad LG. Emergency reversal of anticoagulation after intracerebral hemorrhage. Stroke. 1992;23(7):972-977. (Retrospective case series; 17 patients)
85. Cartmill M, Dolan G, Byrne JL, et al. Prothrombin complex concentrate for oral anticoagulant reversal in neurosurgical emergencies. Br J Neurosurg. 2000;14(5):458-461. (Retrospective)
86. Majeed A, Ågren A, Holmström M, et al. Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study. Blood. 2017;130(15):1706-1712. (Prospective cohort; 84 patients)
87. Zahir H, Brown KS, Vandell AG, et al. Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation. 2015;131(1):82-90. (Randomized controlled trial; 110 patients)
88. Schulman S, Gross PL, Ritchie B, et al. Prothrombin complex concentrate for major bleeding on factor Xa inhibitors: a prospective cohort study. Thromb Haemost. 2018;118(5):842-851. (Prospective cohort; 66 patients)
89. Levi M, Moore KT, Castillejos CF, et al. Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers. J Thromb Haemost. 2014;12(9):1428-1436. (Case control; 35 volunteers)
90. Hall ST, Molina KC. Fixed-dose 4-factor prothrombin complex concentrate: we don’t know where we’re going if we don’t know how to get there. J Thromb Thrombolysis. 2018;46(1):50-57. (Review)
91. Marlu R, Hodaj E, Paris A, et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban. Thromb Haemost. 2012;108(08):217-224. (Case series; 10 patients)
92. Dibu JR, Weimer JM, Ahrens C, et al. The role of FEIBA in reversing novel oral anticoagulants in intracerebral hemorrhage. Neurocrit Care. 2016;24(3):413-419. (Prospective cohort; 127 patients)
93. Lindahl TL, Wallstedt M, Gustafsson KM, et al. More efficient reversal of dabigatran inhibition of coagulation by activated prothrombin complex concentrate or recombinant factor VIIa than by four-factor prothrombin complex concentrate. Thromb Res. 2015;135(3):544-547. (In vitro study)
94. Levi M, Levy JH, Andersen HF, et al. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med. 2010;363(19):1791-1800. (Meta-analysis; 4468 subjects)
95. Dentali F, Marchesi C, Giorgi Pierfranceschi M, et al. Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis. Thromb Haemost. 2011;106(3):429-438. (Meta-analysis; 27 studies, 1032 patients)
96. Harinstein LM, Morgan JW, Russo N. Treatment of dabigatran-associated bleeding: case report and review of the literature. J Pharm Pract. 2013;26(3):264-269. (Case report; 1 patient)
97. Zhou W, Schwarting S, Illanes S, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke. 2011;42(12):3594-3599. (Animal study)
98. Holcomb JB, Tilley BC, Baraniuk S, et al. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA. 2015;313(5):471-482. (Randomized controlled trial; 680 patients)
99. van Ryn J, Sieger P, Kink-Eiband M, et al. Adsorption of dabigatran etexilate in water or dabigatran in pooled human plasma by activated charcoal in vitro. Blood. 2009;114:1065. (In vitro studies)
100. Wang X, Mondal S, Wang J, et al. Effect of activated charcoal on apixaban pharmacokinetics in healthy subjects. Am J Cardiovasc Drugs. 2014;14(2):147-154. (Case control; 18 subjects)
101. Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e44S-e88S. (Guidelines statement)
102. CRASH-2 trial collaborators, Shakur H, Roberts I, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet Infect Dis. 2010;376(9734):23-32. (Randomized controlled trial; 20,211 patients)
103. CRASH-2 collaborators, Roberts I, Shakur H, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet Infect Dis. 2011;377(9771):1096-1101. (Randomized controlled trial; 20,211 patients)
104. Clavé A, Fazilleau F, Dumser D, et al. Efficacy of tranexamic acid on blood loss after primary cementless total hip replacement with rivaroxaban thromboprophylaxis: a case-control study in 70 patients. Orthop Traumatol Surg Res. 2012;98(5):484-490. (Case-control study; 70 patients)
105. Wang J-W, Chen B, Lin P-C, et al. The efficacy of combined use of rivaroxaban and tranexamic acid on blood conservation in minimally invasive total knee arthroplasty a double-blind randomized, controlled trial. J Arthroplasty. 2017;32(3):801-806. (Prospective case control; 70 patients)
106. Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369(13):1206-1214. (Randomized controlled trial; 252 patients)
107. Di Biase L. Use of direct oral anticoagulants in patients with atrial fibrillation and valvular heart lesions. J Am Heart Assoc. 2016;5(2). (Review)
108. Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 135(25):e1159-e1195.(Guideline)
109. Beyer-Westendorf J, Michalski F, Tittl L, et al. Pregnancy outcome in patients exposed to direct oral anticoagulants - and the challenge of event reporting. Thromb Haemost. 2016;116(4):651-658. (Review)
110. Fordyce CB, Hellkamp AS, Lokhnygina Y, et al. On-treatment outcomes in patients with worsening renal function with rivaroxaban compared with warfarin: insights from ROCKET AF. Circulation. 2016;134(1):37-47. (Randomized controlled trial re-analysis; 12,612 patients)
111. Fox KAA, Piccini JP, Wojdyla D, et al. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J. 2011;32(19):2387-2394. (Randomized controlled trial; 14,264 patients)
112. Sarratt SC, Nesbit R, Moye R. Safety outcomes of apixaban compared with warfarin in patients with end-stage renal disease. Ann Pharmacother. 2017;51(6):445-450. (Retrospective cohort; 160 patients)
113. Kimachi M, Furukawa TA, Kimachi K, et al. Direct oral anticoagulants versus warfarin for preventing stroke and systemic embolic events among atrial fibrillation patients with chronic kidney disease. Cochrane Database Syst Rev. 2017;11:CD011373. (Cochrane review)
114. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scientific rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2016;47(2):581-641. (Scientific advisory statement)
115. Chen ST, Hellkamp AS, Becker RC, et al. Outcome of patients receiving thrombolytic therapy while on rivaroxaban for nonvalvular atrial fibrillation (from rivaroxaban once daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation). Am JCardiol.2017;120(10):1837-1840. (Case series; 28 patients)
116. Xian Y, Federspiel JJ, Hernandez AF, et al. Use of intravenous recombinant tissue plasminogen activator in patients with acute ischemic stroke who take non-vitamin K antagonist oral anticoagulants before stroke. Circulation. 2017;135(11):1024-1035. (Case series; 251 patients)
117. Purrucker JC, Wolf M, Haas K, et al. Safety of endovascular thrombectomy in patients receiving non-vitamin K antagonist oral anticoagulants. Stroke. 2016;47(4):1127-1130. (Prospective multicenter observational study; 28 patients)
118. Lip GYH, Banerjee A, Boriani G, et al. Antithrombotic therapy for atrial fibrillation: CHEST guideline and expert panel report. Chest. 2018;154(5):1121-1201. (Guidelines)
119. Lip GY, Frison L, Halperin JL, et al. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score. J Am Coll Cardiol.2011;57(2):173-180. (Observational cohort; 7329 patients)
120. O’Brien EC, Simon DN, Thomas LE, et al. The ORBIT bleeding score: a simple bedside score to assess bleeding risk in atrial fibrillation. Eur Heart J. 2015;36(46):3258-3264. (Observational cohort; 7411 patients)
121. Hijazi Z, Oldgren J, Lindbäck J, et al. The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study. Lancet Infect Dis. 2016;387(10035):2302-2311. (Randomized controlled trial re-analysis; 14,537 patients)
122. Chai-Adisaksopha C, Hillis C, Lim W, et al. Hemodialysis for the treatment of dabigatran-associated bleeding: a case report and systematic review. J Thromb Haemost. 2015;13(10):1790-1798. (Review)
123. Sakamoto Y, Koami H, Miike T. Monitoring the coagulation status of trauma patients with viscoelastic devices. J Intensive Care. 2017;5:7. (Review)
124. Cotton BA, Faz G, Hatch QM, et al. Rapid thrombelastography delivers real-time results that predict transfusion within 1 hour of admission. J Trauma. 2011;71(2):407-414. (Prospective study; 272 patients)
125. Solbeck S, Ostrowski SR, Stensballe J, et al. Thrombelastography detects dabigatran at therapeutic concentrations in vitro to the same extent as gold-standard tests. Int J Cardiol. 2016;208:14-18. (In vitro study; 8 subjects)
126. Seyve L, Richarme C, Polack B, et al. Impact of four direct oral anticoagulants on rotational thromboelastometry (ROTEM). Int J Lab Hematol. 2018;40(1):84-93. (In vitro study)
127. Xu Y, Wu W, Wang L, et al. Differential profiles of thrombin inhibitors (heparin, hirudin, bivalirudin, and dabigatran) in the thrombin generation assay and thromboelastography in vitro. Blood Coagul Fibrinolysis. 2013;24(3):332-338. (In vitro study)
128. Cotton BA, McCarthy JJ, Holcomb JB. Acutely injured patients on dabigatran. N Engl J Med. 2011;365(21):2039-2040. (Letter)
129. Milling TJ, Kaatz S. Preclinical and clinical data for factor Xa and “universal” reversal agents. Am J Med. 2016;129(11 Suppl):S80-S88. (Review)
130. Ansell JE, Bakhru SH, Laulicht BE, et al. Single-dose ciraparantag safely and completely reverses anticoagulant effects of edoxaban. Thromb Haemost. 2017;117(2):238-245. (Randomized controlled trial; 80 patients)
131. Ansell JE, Bakhru SH, Laulicht BE, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med. 2014;371(22):2141-2142. (Letter)
132. Coll-Vinent B, Martín A, Sánchez J, et al. Benefits of emergency departments’ contribution to stroke prophylaxis in atrial fibrillation: the EMERG-AF Study (emergency department stroke prophylaxis and guidelines implementation in atrial fibrillation). Stroke. 2017;48(5):1344-1352. (Prospective cohort; 1162 patients)
133. Kahler ZP, Beam DM, Kline JA. Cost of treating venous thromboembolism with heparin and warfarin versus home treatment with rivaroxaban. Acad Emerg Med. 2015;22(7):796-802. (Case control; 97 patients)
134. Beam DM, Kahler ZP, Kline JA. Immediate discharge and home treatment with rivaroxaban of low-risk venous thromboembolism diagnosed in two U.S. emergency departments: a one-year preplanned analysis. Acad Emerg Med. 2015;22(7):788-795. (Prospective cohort; 106 patients)
135. Wolf SJ, Hahn SA, Nentwich LM, et al. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with suspected acute venous thromboembolic disease. Ann Emerg Med. 2018;71(5):e59-e109. (Clinical policy)
136. Howard L, Barden S, Condliffe R, et al. British Thoracic Society guideline for the initial outpatient management of pulmonary embolism (PE). Thorax. 2018;73(Suppl 2):ii1-ii29. (Guideline)
137. Aujesky D, Obrosky DS, Stone RA, et al. Derivation and validation of a prognostic model for pulmonary embolism. Am J Respir Crit Care Med. 2005;172(8):1041-1046. (Retrospective cohort; 221 patients)
138. Zondag W, Mos ICM, Creemers-Schild D, et al. Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study. J Thromb Haemost. 2011;9(8):1500-1507. (Prospective cohort; 297 patients)
139. Jiménez D, Aujesky D, Moores L, et al. Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med. 2010;170(15):1383-1389. (Retrospective cohort; 995 patients)
140. Frank Peacock W, Coleman CI, Diercks DB, et al. Emergency department discharge of pulmonary embolus patients. Acad Emerg Med. 2018;25(9):995-1003. (Randomized controlled trial; 114 patients)
141. Lamberts M, Staerk L, Olesen JB, et al. Major bleeding complications and persistence with oral anticoagulation in non-valvular atrial fibrillation: contemporary findings in real-life Danish patients. J Am Heart Assoc. 2017;6(2). (Cohort study; 54,321 patients)
142. Yao X, Abraham NS, Sangaralingham LR, et al. Effectiveness and safety of dabigatran, rivaroxaban, and apixaban versus warfarin in nonvalvular atrial fibrillation. J Am Heart Assoc. 2016;5(6). (Cohort study; 125,243 patients)