Oral Anticoagulant Reversal Agents Click here for title Oral Anticoagulant Reversal Agents Click here for subtitle Emmanuel Markakis, Pharm.D., BCPS Clinical Pharmacy Program Manager PGY1 Residency Director Boca Raton Regional Hospital

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

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

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?

Why PCCs are Moving Upstream in Therapy

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??

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

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;124:1573-1579 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

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

Several Things to Consider When Managing Anticoagulation in the Perioperative Setting

Several Things to Consider When Evaluating the Surgery / Procedure

When Should a Patient STOP Anticoagulants Prior to a Procedure?

Reference Chart

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?

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)

References