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
- The Working Group on Perioperative Haemostasis, 2013
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.
Reversing anticoagulant therapy.
Managing bleeding in anticoagulated patients in the emergency care setting.
In this month’s issue of Hematology there’s a good discussion of how to identify and manage patients with a trauma-induced coagulopathy. Check it out.
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.)?