1. Oral Anticoagulant Reversal Agents
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Oral Anticoagulant Reversal Agents
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Emmanuel Markakis, Pharm.D., BCPS
Clinical Pharmacy Program Manager
PGY1 Residency Director
Boca Raton Regional Hospital

2. Objectives Define Prothrombin Complex Concentrates
Review the reversal agents used and studied to reverse oral anticoagulants
Establish timeframes when to use reversal agents for oral anticoagulant reversal

3. Definitions Name Definition
3 Factor Prothrombin Complex Concentrate (PCC)
Reverses the effects of factors II, IX, X
4 Factor PCC
Reverses the effects of factors II, VII, IX, X
Unactivated PCC
Reduced prothrombic effect
Activated PCC
Has prothrombic activy
Reversal Agent
Agent given to counteract/reverse the effects of a source medication/medication effects

4. Let’s Begin with an Assessment
A 58 yo F patient taking apixaban is diagnosed with ICH. Her last dose of apixaban was over 24 hours ago. She has normal renal function. The team asks you if she is a candidate for the hospital’s Factor Prothrombin Complex Concentrate drug. Your answer is:
Yes she is a candidate, even though off-label, the drug works
I’m not sure yet, we need an INR first before I give an opinion
No she is not a candidate, the apixaban likely wore off by now
What’s Pharmacy’s extension?

5. Why PCCs are Moving Upstream in Therapy

6. The Reversal Agents Reveral Agent Reverses….. Dose Comments
3 Factor PCCs
Profilnine
Warfarin
INR <2: 20 units/kg
INR 2 to 4: 30 units/kg
INR >4: 50 units/kg
Needs Vit K
Bebulin
4 Factor PCC
Kcentra
Xa Inhibitors
INR 2 to <4: 25 units/kg; maximum dose: 2,500 units
INR: 4 to 6: 35 units/kg; maximum dose: 3,500 units
INR: >6: 50 units/kg; maximum dose: 5,000 units
50 units/kg IV x 1
FEIBA
No Vit K needed
Andexanet Alfa
Approved May 3rd!
400mg IV for low doses of DOACs x 1 followed by Infusion or 800mg IV x 1 for high doses of DOACs followed by infusion
What will final dose be??
Idarucizumab
Dabigatran
5g x 1
May need PCC??

7. Why is Vitamin K Needed with PCCs?
Vitamin K is needed to prevent the INR from rising after dosing of PCC

8. Quick Clinical Trial Summary
Reversal Agent
Summary of Literature
Kcentra
Only evaluated in healthy volunteers, never in real cases; patients took rivaroxaban and then given Kcentra, time to normal evaluated
Circulation. 2011;124:
FEIBA
Only evaluated in healthy volunteers, never in real cases; patients took rivaroxaban and then given FEIBA, time to normal evaluated
Thromb Haemost 2012; 108: 217–224
Andexanet Alfa
Idarucizumab
For patients in (1) admitted with bleeding, median time to cessation of bleeding was 11.4 hours.
For those undergoing urgent procedures, 92% were reported to have normal intraoperative hemostasis after receiving idarucizumab.
NEJM, June 22,2015

9. Approval Delays Chronology
May 3rd, 2018 Approval
August 2017
February 2018
Why?
FDA Wanted more manufacturing technique information
FDA Wanted more data on enoxaparin and edoxaban
Why?
FDA evaluating new data submitted by Portola

10. Several Things to Consider When Managing Anticoagulation in the Perioperative Setting

11. Several Things to Consider When Evaluating the Surgery / Procedure

12. When Should a Patient STOP Anticoagulants Prior to a Procedure?

13. Reference Chart

14. Back to Our Question
A 58 yo F patient taking apixaban is diagnosed with ICH. Her last dose of apixaban was over 24 hours ago. She has normal renal function. The team asks you if she is a candidate for the hospital’s 4 Factor Prothrombin Complex Concentrate drug. Your answer is:
Yes she is a candidate, even though off-label, the drug works
I’m not sure yet, we need an INR first before I give an opinion
No she is not a candidate, the apixaban likely wore off by now
What’s Pharmacy’s extension?

15. Take Home Points Warfarin: Kcentra requires INR for dosing
Kcentra does contain heparin (watch for HIT patients)
Vitamin K MUST be IV, cannot be SQ or IM
Rivaroxaban/Apixaban/Edoxaban
Kcentra dosing is 50units/kg IV x 1 dose
NO VITAMIN K NEEDED
No clinical benefit in most patients with Kcentra if patient hasn’t had the anticoagulant >24 hours (except in severe renal insufficiency)
Endaxanet Alfa Availability? Lauch? Prothrombic Effects 18% of patients
Dabigatran
Do not use Kcentra or any PCC, use Idarucizumab (Praxbind)
No clinical benefit with idarucizumab if patient hasn’t had the anticoagulant >24 hours (>72 hours for elderly or creatinine clearance <50ml/min)

16. References