Novel Anticoagulants and Bleeding in the Emergency Department

Introduction

  • 4.2 million Americans were taking an anticoagulant in 2007
  • 3% of all patients (with 9% of patients >65 yrs old) presenting to trauma centers are anticoagulated
  • 50% of anticoagulated intracranial hemorrhage patients have increased/continued bleeding for more than 12-24 hrs

Novel Oral Anticoagulants (NOACs)

Dabigatran (Pradaxa)
Direct thrombin inhibitor used for non-valvular atrial fibrillation only
  • Re-Ly Trial: Reduced major bleeding compared to warfarin, superior stroke prevention
  • Onset 2h; half-life 12-15h; renal excretion
Rivaroxaban (Xarelto)
Cofactor Xa inhibitor
  • FDA approved for non-valvular atrial fibrillation, venous thromboembolism and prophylaxis
  • Onset 3h; half-life: 6-9 hrs, hepatic and renal metabolism
  • Magellan Trial: Effective means of DVT prophylaxis
  • ROCKET: AF study
    • Same as warfarin for preventing stroke
    • Similar rates of major bleeding, but fewer intracranial bleeds and fewer overall fatal bleeding episodes
Apixaban (Eliquis)
Cofactor Xa inhibitor
  • FDA approved for non-valvular atrial fibrillation and venous thromboembolism
  • Onset 3h; half-life 12-13h
  • Reduced stroke rates, similar bleeding rates with fewer fatal bleeding episodes

Reversal Strategies

  • Normal PTT with a normal INR excludes supratherapeutic levels of NOAC when measured at least 3hrs after last dose
  • Balance between bleeding and thrombosis
Vitamin K
Restores clotting factor production
Fresh Frozen Plasma
Restores clotting factors
  • Commonly used and poorly evidence supported, futile in NOAC reversal
  • Requires ABO compatibility and often thawing
  • Reliable replacement for severe bleeding: 30ml/kg, meaning 4 to 12 units!
  • Time to correction of warfarin with FFP => 13-48 hrs
Recombinant Factor VIIa (rFVIIa)
Triggers final common pathway => thrombin production
  • Rosovsky and Crowther: Rapid correction of INR, but clinical implications unclear, recommend against routine use for warfarin reversal
  • Complicating thrombosis reported in 10-20% of patients undergoing reversal therapy
Prothrombin Complex Concentrate (PCC)
  • Stored as powder, can be prepared in minutes
  • No ABO compatibility testing needed
  • Volumes (100ml) are small, quickly administered
  • Reversal possible in 15 minutes, PT/PTT can be rechecked
  • 1-4% thrombosis risk
  • 3 PCC replaces II, IX, X
  • FEIBA (aPCC) replaces II, IX, X, C, and activated VII
  • 4 PCC replaces II, VII, IX, X, C & S
  • Many systematic reviews and groups recommend PCC for NOAC reversal, many hospital protocols have been developed (Chapel Hill)
  • PCC dose: 25-50 U/kg
Hematology Consult
Dialysis for dabigatran-related bleeding
Tranexamic Acid
Procoagulant molecule
  • No good data for this in NOAC bleeds
  • Emergency Med J, 2013 review still recommended giving 1g IV to major bleeds because of absence of major side effects

Warfarin (Vit. K Antagonist) Reversal

  • American College of Chest Physicians, 2012 and American Heart Association and Stroke Association 2010 guidelines for warfarin bleeds
    • Minor bleed and INR 4-10, hold warfarin only
    • Minor bleed and INR >10, 2mg oral vitamin K
    • Major bleed: 4 PCC instead of FFP, and 5-10mg IV vitamin K
    • Recommend against activated factor VII as a single reversal agent

Don’t Forget the Basics

  • General management still critical: stop anticoagulants, protect kidneys (IVF, no NSAIDS or contrast), manage massive bleeding with PRBCs/FFP/Plts (1:1:1) as needed, PPI for upper GIB, BP for IPH, direct pressure for external bleeds, intervention, etc.
    • The Working Group on Perioperative Haemostasis, 2013
      • Recommends PCC 50U/kg for reversal of serious bleeding caused by NOAC
      • Hemostasis Summit of North America, 2012
        • Oral charcoal if <2hrs after any NOAC ingestion, and must be intubated; based on in-vitro study and case report
        • Recommend 4-PCC (II, VII, IX, X, C and S) and recheck coags after 15-30 min
        • Recommend against FFP, futile in NOAC bleeding

Pearls

  • Use PCC instead of FFP for severe warfarin and NOAC bleeds
  • Assess thrombosis risk, especially when using rFVIIa or aPCC

Further Reading

Dosset LA, Riesel JN, Griffin MR, et al. Prevalence and implications of preinjury warfarin use: analysis of the National Trauma Databank. Arch Surg. 2011; 146 (5): 565-570.

Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Eng J Med. 2011; 365 (11): 981-992.

Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Eng J Med. 2009; 361 (12): 1139-1151.

Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Eng J Med. 2011: 365 (10): 883-891.

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.

CRASH-2 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 randomized controlled trial. Lancet. 2010; 376 (9734): 23-32.

Switzer JA, Rocker J, Mohorn P, et al. Clinical experience with three-factor prothrombin complex concentrate to reverse warfarin anticoagulation in intracranial hemorrhage. Stroke. 2012; 43 (9): 2500-2502.

Kenneth F. Rapid reversal of warfarin-associated hemorrhage in the emergency department by prothrombin complex concentrates. Ann Emerg Med. 2013; 62: 616-626.

Management of hemorrhage complicated by novel oral anticoagulants in the emergency department: case report from the northwestern emergency medicine residency.

Reversing anticoagulant therapy.

Managing bleeding in anticoagulated patients in the emergency care setting.

New oral anticoagulants in the ED setting: a review.

Edited by Alex Koyfman

3 thoughts on “Novel Anticoagulants and Bleeding in the Emergency Department”

  1. Great post! I’ve had a couple Dabigatran ICH requiring dialysis. How does dialysis reversal compare to the other methods you discussed (PCCs, FFP, Vit K, etc.)?

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