1. Care of the Anti-coagulated Trauma Patient Julie Mayglothling, MD, FACEP Emergencies in Medicine March 8 th, 2012

2. Dabigatran, Apixaban, Rivaroxaban- Oh My! Emerging Anticoagulants and Their Impact on Trauma Julie Mayglothling, MD, FACEP Emergencies in Medicine March 8 th, 2012

3. Objectives Discuss evaluation and management of injured patients on anti-coagulant medications Antiplatelet, coumadin, newer anticoagulants Review reversal agents used in anti-coagulated trauma patients Discuss potential reversal of new agents

4. Anti-coagulants

5. The Breakdown… Anticoagulant Anti-platelet Coumadin Dabigatran, Rivaroxaban Severity of Illness Acute hemorrhage/hemodynamically unstable Intracranial Hemorrhage Mildly injured/Asymptomatic Age

6. Anti-platelet Agents

7. 46 year old, on daily ASA, hit in the head with a 2x4

8. Antiplatelet agents 5 studies reviewed (3 of 5 show increased risk) Ages > 50, > 60, no age limit Significant mechanism (fall?) Associated with  morbidity, possibly  mortality Especially in age > 50

9. Major Trauma >1.2 million patients >36,000 warfarin users 4% in 2006 12.8% in patients > 65

10. Major Trauma Warfarin use associated with double mortality (9.3%) Both in all patients and patients > 65 All patients and all injury patterns Most pronounced for TBI patients < 65

11. Warfarin 6 of 8 studies found increased risk of morbidity and mortality with warfarin Especially in elderly patients (regardless of ISS) Level of INR associated with mortality

12. Coumadin in Minor Head Trauma 5 Retrospective studies 65-144 patients in each 2 studies support clinical exam 2 studies state scan regardless of normal neuro exam 1 study uses INR cut-off 2.37 Age certainly a factor Unclear for patients < 50

13. What about a normal head CT? 81 years old Fall with no LOC INR 2.8 Initial CT with no ICH Dispo?

14. To observe, or not to observe… European guidelines European guidelines Negative head CT  24 hours observation followed by a 2 nd head CT (Vos. Eur J Neurol. 2002) Negative head CT  24 hours observation followed by a 2 nd head CT (Vos. Eur J Neurol. 2002) Menditto (Ann Emerg Med 2012) Menditto (Ann Emerg Med 2012) 97 patients with neg head CT (To Obs) 97 patients with neg head CT (To Obs) 5 patients (6%) with delayed bleed 5 patients (6%) with delayed bleed Increased risk with INR > 3 Increased risk with INR > 3

15. Reversal of Anti-Coagulation Anti-platelet agents Platelets Desmopressin (ddAVP) (0.3 mcg/kg) Recombinant activated factor VIIa (big gun…)

16. Thromboelastography (TEG) fibrinolysis Activated clotting time

17. Reversal of Anti-Coagulation Warfarin Vitamin K Fresh Frozen Plasma Cryoprecipitate Prothrombin complex concentrate Activated Factor VIIa

18. Reversal of Anti-Coagulation Vitamin K Cofactor II, VII, IX, X 10 mg IV (no IM or SQ) Full effect 12-24 hours Repeated doses as needed

19. Fresh Frozen Plasma Delayed time to reversal Thawing and cross-matching Risks of Volume overload 10-15 mL/kg = 700 mL = 3 units FFP TRALI ABO incompatibilities

20. Prothrombin Complex Concentrate Concentrate of Factors II, VII, IX, X, Prot C&S Factor IX is the workhorse (dosing) pooled human plasma from healthy donors Half Life: Factor VII: 2-4 hrs Factor IX: 24 hrs Complication rate < 1% Availability in US

21. Activated Factor VIIa Never been formally studied for reversal of warfarin in TBI Non-anticoag pts! Half life ~ 2.5 hours Add Vitamin K and FFP or PCC Role and dose debatable

22. Dabigatran (Pradaxa) Direct thrombin inhibitor (DTI) Better than coumadin Works better! Decreased risk of bleeding No monitoring One dose fits all No dietary interactions No P450

24. What’s important to know? Peak effect 2-3 hours Peak effect 2-3 hours 80% excreted (unchanged) in urine 80% excreted (unchanged) in urine Normal renal function Normal renal function ½ life 13 hours ½ life 13 hours Any renal dysfunction has longer duration Any renal dysfunction has longer duration Measurement (aPTT, TT, ECT) Measurement (aPTT, TT, ECT) Prolonged ACT IN rTEG Prolonged ACT IN rTEG

25. Factor Xa Inhibitors Rivaroxaban Direct competitive inhibitor ROCKET study Similar efficacy and decreased bleeding than coumadin Apixaban Apixaban Direct competitive inhibitor Direct competitive inhibitor Aristotle trial Aristotle trial Decreased stroke, decreased bleeding Decreased stroke, decreased bleeding

26. 26 Figure 1: Site of action of new anticoagulant drugs. From Brighton T. Experimental and clinical pharmacology: new oral anticoagulant drugs – mechanisms of action. Aust Prescr. 2010;33:38-41. Reprinted with permission from Australian Prescriber. Sites of Action of New Anticoagulant Agents

27. Proposed Reversal Agents Dialysis Dialysis Package insert Package insert Logistics??? Logistics??? Activated charcoal (within 2-3 hours) Activated charcoal (within 2-3 hours) Vitamin K Vitamin K FFP FFP PCC PCC Factor VIIa Factor VIIa

28. 28 Figure 1: Site of action of new anticoagulant drugs. From Brighton T. Experimental and clinical pharmacology: new oral anticoagulant drugs – mechanisms of action. Aust Prescr. 2010;33:38-41. Reprinted with permission from Australian Prescriber. Sites of Action of New Anticoagulant Agents

29. The Only Study!!! Cofact (4 factor PCC) Cofact (4 factor PCC) 12 healthy volunteers, Crossover study 12 healthy volunteers, Crossover study Dabigatran or Rivaroxaban Dabigatran or Rivaroxaban Totally reversed Rivaroxaban Totally reversed Rivaroxaban Prolongation of PT reversed Prolongation of PT reversed No effect of Dabigatran No effect of Dabigatran Increased aPTT NOT reversed Increased aPTT NOT reversed No effect on ecarin CT and TT No effect on ecarin CT and TT

30. Recommendations for Reversal Intracranial hemorrhage or life-threatening traumatic hemorrhage Anti-platelet therapy Platelet transfusion (10 pack) Possibly ddAVP (0.3 mcg/kg) Warfarin Vitamin K 10 mg IV + FFP 15 mL/kg Use of PCC may increase in the future rFVIIa role is debatable

31. Reversal of the new guys… Dialysis Dialysis 80% of dabigatran is renally excreted 80% of dabigatran is renally excreted 66% of rivaroxaban 66% of rivaroxaban 25% of apixaban 25% of apixaban

32. Conclusions Patients on oral anti-coagulant therapy have increased morbidity and mortality after trauma Reversal strategies for anti-platelet and warfarin are fairly well established New DTI’s and Factor Xa inhibitors pose a unique challenge Dialysis (not always feasible) PCC (possible but poor data) Factor VIIa (unclear)

33. Thank You