Disclosure I have no actual or potential conflict of interest in relation to this presentation. Sarah Lombardo, MD., MSc. General Surgery, University of Utah September 9, 2015 Objectives Outline Recognize common oral anticoagulants (OATs) Understand mechanisms of common OATs Understand indications and dosing of reversal agents for common OATs Understand the risks associated with reversal Understand applicability of reversal agents in the trauma patient Mechanisms of traditional and novel OATs Reversal strategies R-I-S-K, find out what it means to me Reversal in the hemodynamically unstable trauma patient Reversal in the TBI patient
Coagulation Cascade 1. Vitamin K inhibitor The Cascade 2. Direct Xa inhibitor 3. Direct thrombin inhibitor The Usual Suspects Review of Oral Anticoagulants Warfarin Rivaroxaban Apixaban Edoxaban Clopidogrel
Warfarin (aka: Coumadin) Rivaroxaban (aka: Xarelto) Mechanism: vitamin K antagonist Indications: 1) atrial fibrillation 2) VTE prophylaxis 3) VTE treatment Half-life: 20-60 hours (effective) Dosing: Titrated to goal INR 2-3, or 2.5 to 3.5 Tests: INR/PT Mechanism: direct Factor Xa inhibitor Indications: 1) atrial fibrillation 2) VTE prophylaxis Half-life: 5-9 hours (11-13 hour > 65 yo) Dosing: 10 to 20mg, q12 to q24h Tests: anti-factor Xa activity, PT, TEG Apixaban Dabigatran (aka: Pradaxa) Mechanism: direct Factor Xa inhibitor Mechanism: direct thrombin inhibitor Indications: 1) atrial fibrillation 2) VTE prophylaxis 3) VTE treatment Indications: 1) atrial fibrillation 2) VTE prophylaxis 3) VTE treatment Half-life: 8-15 hours Dosing: 2.5 to 5mg, q12 to q24h Tests: PT, PTT, INR, anti-factor Xa activity, TEG Half-life: 14-17 hours Dosing: 150mg bid Tests: ecarin clot time (ECT), PTT, thrombin time, TEG
Clopidogrel (aka: Plavix) Mechanism: irreversibly blocks ADP release Indications: 1) CAD, including ACS, stent Half-life: 6 hours 2) PAD 3) Stroke prevention Dosing: 75mg daily Tests: platelet function testing, TEG Thrombin time Reversal Strategies Reversal Strategies Antidote Vitamin K Idarucizumab? Factor Replacement FFP PCC Factor VIIa
Factor Replacement FFP (aka: plasma) Fresh Frozen Plasma (FFP) Prothrombin Complex Concentrate (PCC) Activated Prothrombin Complex Concentrate (apcc) Activated Factor VII (FVIIa) Indications: Hemorrhage associated with warfarin use, deficiency of multiple coagulation factors, and massive transfusion Brand N/A Kcentra FEIBA NovoSeven Factors +/- II, V, VII, IX, X, XI, vwf, fibrinogen High volume Leukocytes Thaw time II, VII, IX, X II, VIIa, IX, X rviia Low volume Thrombosis Low volume Thrombosis Low volume Cost Efficacy Dosing: time. Target factors at >30% normal. Often requires ~15 ml/kg of FFP. 30 min thaw time. 30 min transfusion PCC (aka: Kcentra) apcc (aka: FEIBA) Indications: Dosing: Urgent reversal of Vitamin K antagonist in patients with major bleed or for urgent procedure INR 2 to < 4: 25 units/kg (max 2500 units) INR 4 to 6: 35 units/kg (max 3500 units) INR >6: 50 units/kg (max 5000 units) Administer with Vitamin K. Repeat dosing not recommended. Indications: Dosing: Hemorrhage, peri-procedural, or prophylaxis for bleeding events in patients with hemophilia 25-100 units/kg, may repeat Correction of INR to < 1.5 with single dose within approximately 30 minutes
rfviia (aka: NovoSeven) Warfarin (aka: Coumadin) Indications: Dosing: Hemorrhage and perioperative management of hemophiliacs, congenital FVII deficiency, and Glanzmann s thrombocytopenia 10 to 100 mcg/kg Administer with IV Vitamin K. May need to repeat dosing based on INR. Mechanism: Vit K antagonist Reversal agents: vitamin K Dialyzable: No Factors: FFP, PCC Warfarin (aka: Coumadin) Non-bleeding patient Warfarin (aka: Coumadin) Bleeding patient INR < 5 INR 5-9 INR >9 Minimal INR > 5 Urgent or procedural Life threatening Hold next dose Hold next dose Oral Vit K (1-2.5mg) Hold next dose Oral Vit K (2.5-5mg) Hold next dose Vitamin K (IV or PO) Hold next dose Vitamin K (10mg IV) PCC (4- factor) PCC DDAVP FFP/Plts/R BC Hold next dose Vitamin K (10mg IV) Tranexamic acid
Rivaroxaban (aka: Xarelto) Rivaroxaban (aka: Xarelto) Mechanism: FXa inhibitor Reversal agent: None Dialyzable: No Factors: PCC, apcc, rfviia Phase 1 12 subjects Cross-over study Eerenberg et. al., Circulation 2011 Rivaroxaban (aka: Xarelto) Apixaban Mechanism: FXa inhibitor Reversal agent: None Dialyzable: No Factor: PCC, apcc, rfviia Eerenberg et. al., Circulation 2011
Apixaban Apixaban In vitro 10 healthy subjects Apixaban added to blood samples MacDonald and Luddington, Semin Thromb Hemost. 2010 Apixaban Apixaban Escolar et. al., PLoS One. 2013 Escolar et. al., PLoS One. 2013
Apixaban Dabigatran (aka: Pradaxa) Mechanism: thrombin inhibitor Reversal agent: idarucizumab Dialyzable: Yes (>50%, 4 hours) Factor : apcc, rfviia Escolar et. al., PLoS One. 2013 Rivaroxaban (aka: Xarelto) Rivaroxaban (aka: Xarelto) Phase 1 12 subjects Cross-over study Eerenberg et. al., Circulation 2011 Eerenberg et. al., Circulation 2011
Dabigatran (aka: Pradaxa) Monoclonal antibody to dabigatran Prospective cohort Eerenberg et. al., Circulation 2011 90 subjects Group A (n=51) = life-threatening bleed Group B (n=39) = required procedure Thrombin time Ecarin clot time
Clopidogrel (aka: Plavix) Reversal Summary 4- Factor PCC Activated PCC Activated Factor VII Antidote Mechanism: irreversible platelet aggregation inhibitor Reversal agent: None Dialyzable: No Factor: platelets, desmopressin (DDAVP) Brand name Kcentra FEIBA NovoSeven N/A Factors II, VII, IX, X II, VIIa, IX, X VIIa N/A Coagulopathy Reversal Warfarin Yes Yes Yes Vitamin K Rivaroxaban Maybe Yes Maybe None Apixaban Maybe Yes Maybe None Dabigatran No Maybe Maybe Idarucizumab OATs and Trauma Outcomes Bleeding rates on novel OATs vs. warfarin are comparable Spontaneous vs. trauma-associated R-I-S-K OAT use associated with worse outcomes Warfarin vs. antiplatelet agents Elderly TBI Early reversal may reduce hemorrhage progression
Risks of Rapid Reversal FFP PCC, apcc rfviia Fluid overload Viral transmission Thromboembolic events Arterial thrombosis Clinical Case Allergic reaction Clinical Case: Ruth Clinical Case: Imaging 80 yo F Transfer: new onset stoke-like symptoms PMHx: polio, HTN, valve replacement Meds: ASA 81mg, coumadin Physical exam Old bruising over left eyebrow No neural deficits Intermittent slurring of words Waxing waning exam Labs INR 2.3 Plts 198 Hgb 13.1 Imaging.
Clinical Case: Management Traumatic Brain Injury Questions Actively bleeding? Symptomatic? Next steps Hold anticoagulants Vitamin K Repeat CT head Consult to Neurosurgery Reversal not shown to improve outcomes, but may reduce progression EAST guidelines Begin therapy to correct INR within 2 hours INR at < 1.6 by 4 hours Do not reverse patients with head injury who lack radiologic findings Platelet transfusion not shown to reduce mortality or alter outcomes Concerns with prior study designs Recommendations: 5-10 U platelets, desmopressin References Baumann-Kreuziger LM, Morton CT, Dries DJ. New anticoagulants: a concise review. J Trauma Acute Care Surg, 2012;73(4):983-92. Erenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healhty subjects. Circulation, 2011;124:1573-79. Escolar G, Fernandez-Gallego V, Arellano-Rodrigo E, et al. Reversal of apixaban induced alteraions in hemostasis by different coagulation factor concentrates: significance of studies in vitro with circulating human blood. PLoS ONE, 2013;8(11):e78696. Freeman WD, Aguilar MI, Weitz J.. Reversal of anticoagulation in warfarin-associated intracranial hemorrhage. In: UpToDate, Leung LLK, Kasner SE (Eds), UpToDate, Waltham, MA. (Accessed on September 5, 2015.). Grandhi R, Harrison G, Voronovich Z, et al. Preinjury warfarin, but not antiplatelet medications, increases mortality in elderly traumatic brain injury patients. J Trauma Acute Care Surg, 2014;78(3):614-21. Hull RD, Garcia DA. Management of warfarin-associated bleeding or supratherapeutic INR. In: UpToDate, Leung LLK (Ed), UpToDate, Waltham, MA. (Accessed on September 5, 2015.). MacDonald SG, Luddington RJ. Critical factors contributing to the thromboelastography trace. Semin Thromb Hemost, 2010;36(7):712-22. McCoy CC, Lawson JH, Shapiro ML. Management of anticoagulation agents in trauma patients. Clin Lab Med, 2014;34(3):563-74. Moorman ML, Nash JE, Stabi KL. Emergency surgery and trauma in patients treated with the new oral anticoagulants: dabigatran, rivaroxaban, and apixaban. J Trauma Acute Care Surg, 2014;77(3):486-94. Pollack CV, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med, 2015;373:511-20. Schochl H, Voelckel W, Maegele M, et al. Endogenous thrombin potential following hemostatic therapy with 4-factor prothrombin complex concentrate: a 7-day observational study of trauma patients. Critical Care, 2014;18:R147.