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Emergency Management of Patients Taking Direct Oral
Anticoagulants
Brian K. Yorkgitis, PA-C, DOAssistant Professor of SurgeryDivision of Acute Care Surgery
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Objectives
• Understand the pharmacologic properties of Direct Oral Anticoagulants (DOAC’s)
• Indications for use of DOAC’s• Describe reversal strategies of the DOAC’s
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History
• Traditional oral anticoagulation was with Vitamin K Antagonists (VKA)• Required close monitoring• Narrow therapeutic window• Significant drug-drug and drug-food interaction• Long T1/2 (20-60 hours)• Genetic variations in the VKORC1 gene (single
biggest predictor of warfarin dose) are associated with differences in warfarin doses
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New Kids on the Block
• Direct Oral Anticoagulant (DOAC)• Novel Oral Anticoagulant (NOAC)• Non-Vitamin K Antagonist Oral Anticoagulants
(NOAC)• 2013, over 60% of all new prescriptions for
oral anticoagulants were NOACs
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Why the Enthusiasm?
• Predictable pharmacodynamics and pharmacokinetics– No routine coagulation monitoring
• Very few interactions with common medications• Ease of doing (fixed dosing)• Huge marketing campaigns• Better than conventional therapy?• Lower or similar risk of bleeding events
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Dabigatran• Pradaxa• Factor IIa inhibitor
– Inhibits both free and fibrin bound thrombin• Prodrug• Renal excretion• Approved use in US
– NVAF (RE-LY)- embolic events 1.69% vs. 1.53%/yr• Major bleed 3.36 vs. 2.71%/yr, Hemorrhagic CVA 0.38 vs. 0.1%/yr
– Prevention of VTE after TKA/THA– Treatment of VTE
• After 5-10 days of parenteral AC– Reduction of recurrent risk of VTE
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Rivaroxaban
• Xeralto• Oral direct Xa inhibitor• Eliminated via renal (66%) and hepatic (33%) • Approved use in US– NVAF– VTE treatment– VTE prophylaxis
• THA/TKA– Reduction of recurrent risk of VTE
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Apixaban
• Eliquis• Oral direct factor Xa inhibitor• Predominately metabolized by the liver and excreted
in urine and feces• Pregnancy category B• Approved use in US– NVAF– VTE treatment– VTE prophylaxis
• THA/TKA
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Edoxaban
• Savaysa• Direct factor Xa inhibitor• Elimination 50% renal, 50% hepatic• Approved use in US– NVAF– Treatment of VTE • After 5-10 days of parenteral AC
– Reduction of recurrent risk of VTE
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Laboratory Testing
• Dabigatran– Dilute thrombin time or ecarin-based assay– Thrombin time– aPTT– TEG
• Xa Inhibitors– Anti-Xa assay with drug specific calibration
• Not available– PT– TEG
Samuelson CHEST 2016
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AF: CVA or Systemic Emboli
• Decreased or similar rate of events
Ruff, Lancet 2013
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Bleeding
Ruff, Lancet 2013Poposka ESC 2013
ROCKET AF RE-LY 150mg ARISTOLERivaroxaban Warfarin Dabigatran Warfarin Apixaban Warfarin
Intracranial Bleed 3.6 3.4 3.13 3.76 2.13 3.09
HR 1.04 (0.90-1.20), p 0.58 HR 0.92 (0.81-1.07), p 0.31 HR 0.96 (0.60-0.80) p<0.01
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NOAC and VTE
• CHEST Guidelines
CHEST 2016; 149(2):315-352
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VTE Treatment
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Indications and Dosing
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Duration of Therapy After VTE
Proximal DVT or PE
ProvokedSurgery or
Transient RF
3 months(Grade 1B)
Unprovoked
Low bleeding
risk
Extended therapy(first VTE - Grade 2B,
second VTE - Grade 1B)
Mod bleeding
risk
Extended therapy (first VTE - Grade 2B,
second VTE - Grade 2B)
High bleeding
risk
3 months(first VTE - Grade 1B, second VTE -
Grade 2B)
Isolated Distal DVT
Mild symptoms
or high bleeding
risk
Serial imaging x2 weeks
(Grade 2C)
Extending thrombus
Anticoagulate(Grade 1B, 2C)
Severe symptoms or risk for extension
Anticoagulate(Grade 2C)
Cancer-associated
Extended therapy(Grade 1B)
Upper extremity DVT
Anticoagulate(Grade 2C)
No CancerNOAC>VKA
Grade 2B
CHEST 2016;149(2):315-352
CancerLMWH>VKA/
NOACGrade 2C
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Alternative Anticoagulation
• Abrupt cessation of NOAC associated with increase risk of thrombosis
• High risk– Proximal venous thrombosis with or without
pulmonary embolism in the previous 3 mo.– Recurrent unprovoked VTE– Patients with AF with history of cardio-embolic
disease
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Thromboembolic Risk Categories
Ferrandis, Thromb Haemost, 2013
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Hemorrhage Management
• Degree of hemorrhage• Location of hemorrhage• Timing of last dose of DOAC• Hemodynamic stability• Risk of thrombosis• Normal PT/aPTT likely excludes significant
effect of the DOAC
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• Retrospective review• 112 DOAC vs. 373 warfarin• Similar patient characteristics
Maung Trauma 2016
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Prothrombin Complex Concentrates
• Concentrated plasma product that contains clotting factors in varying amounts
• Activated vs. Non-activated• 3 Factor- II, IX, X• 4 Factor- II, VII, IX, X• Can contain anticoagulants– heparin, antithrombin, protein C and S
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Kcentra outside US
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PCC for VKA Reversal• Provide a more rapid decrease in INR values as compared to FFP
– 2012 CHEST Antithrombotic Guidelines recommend the use of PCC over FFP for patients with life-threatening bleeds while on VKA therapy
– FFP contains lower amounts of clotting factors II, VII, IX, X when compared to PCC• Amount of FFP required to administer an equivalent factor replacement dose
received in PCC products would be 8–16 units of FFP• Could lead to volume overload
• Does not require thawing• Some hospitals may not have a quantity of FFP needed for
complete reversal• Reduced pathogen transmission• Leukocyte free- less transfusion/TRALI risk
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Specific Reversal Agents• Idarucizumab (Praxbind)
– Antibody fragment against dabigatran by mimicking thrombin and has a high affinity for dabigatran (350x)
– Immediate effect– Antidote does not bind known thrombin substrates and has no
activity in coagulation tests or platelet aggregation• Andexanet alfa (not available)
– Mimics factor Xa- binds Xa inhibitors– ANNEXA trials
• Arapazine/Ciraparatag (not available)– Universal reversal agent
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Approach to Bleeding
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Ischemic CVA on DOAC’s
• Assess time window since last dose of DOAC– Thrombolytic therapy associated with increased
bleeding risk within 48h of last dose• If uncertain of last dose time– Prolonged PT for Xa inhibitors- do not administer– Prolonged aPTT for DTI- do not administer
EHRA practical guide on the use of new oral anticoagulants in patients with NVAF
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Procedures
• LP- ideally 48h since last dose– Emergent- perform at trough
• Central venous access– Use compressible site under US guidance
• Incision and Drainage– Attempt to perform at trough
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Drug-Drug Interactions
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Drug-Drug Interaction
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Take Home Message
• Lower risk of bleeding with NOAC• Dabigatran is only NOAC with specific reversal• PCC can be given off-label for reversal of DOAC– Dabigatran: Idarucizumab>FEIBA>PCC– Xa inhibitors: PCC
• Assess risk of thromboembolic event• TIME of last dose is essential