Direct oral anticoagulants (DOACs) like dabigatran, rivaroxaban, apixaban, and edoxaban are increasingly used alternatives to warfarin for stroke prevention in atrial fibrillation and treatment of venous thromboembolism. They have more predictable pharmacokinetics than warfarin, avoiding the need for routine monitoring, but specific reversal agents are limited. Idarucizumab is approved for dabigatran reversal while prothrombin complex concentrates may help reverse factor Xa inhibitors like rivaroxaban off-label. Management of bleeding depends on its severity, location, time since last dose, and thrombosis risk. Procedures

1. Emergency Management of
Patients Taking Direct Oral
Anticoagulants
Brian K. Yorkgitis, PA-C, DO
Assistant Professor of Surgery
Division of Acute Care Surgery

2. Objectives
• Understand the pharmacologic properties of
Direct Oral Anticoagulants (DOAC’s)
• Indications for use of DOAC’s
• Describe reversal strategies of the DOAC’s

3. 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

4. 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

5. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. AF: CVA or Systemic Emboli
• Decreased or similar rate of events
Ruff, Lancet 2013

13. Bleeding
Ruff, Lancet 2013
Poposka ESC 2013
ROCKET AF RE-LY 150mg ARISTOLE
Rivaroxaban 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

14. NOAC and VTE
• CHEST Guidelines
CHEST 2016; 149(2):315-352

15. VTE Treatment

16. Indications and Dosing

17. Duration of Therapy After VTE
Proximal
DVT or PE
Provoked
Surgery 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 Cancer
NOAC>VKA
Grade 2B
CHEST
2016;149(2):315-352
Cancer
LMWH>VKA/
NOAC
Grade 2C

18. 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

19. Thromboembolic Risk Categories
Ferrandis, Thromb Haemost, 2013

20. 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

21. • Retrospective review
• 112 DOAC vs. 373 warfarin
• Similar patient characteristics
Maung Trauma 2016

22. 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

23. Kcentra
outside US

24. 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

25. 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

26. Approach to Bleeding

27. 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

28. 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

29. Drug-Drug Interactions

30. Drug-Drug Interaction

31. 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