Emergency Management of Patients Taking Direct Oral

Anticoagulants

Brian K. Yorkgitis, PA-C, DOAssistant Professor of SurgeryDivision of Acute Care Surgery

Objectives

• Understand the pharmacologic properties of Direct Oral Anticoagulants (DOAC’s)

• Indications for use of DOAC’s• Describe reversal strategies of the DOAC’s

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

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

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

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

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

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

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

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

AF: CVA or Systemic Emboli

• Decreased or similar rate of events

Ruff, Lancet 2013

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

NOAC and VTE

• CHEST Guidelines

CHEST 2016; 149(2):315-352

VTE Treatment

Indications and Dosing

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

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

Thromboembolic Risk Categories

Ferrandis, Thromb Haemost, 2013

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

• Retrospective review• 112 DOAC vs. 373 warfarin• Similar patient characteristics

Maung Trauma 2016

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

Kcentra outside US

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

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

Approach to Bleeding

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

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

Drug-Drug Interactions

Drug-Drug Interaction

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