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