Now We Got Bad Blood: New Anticoagulant Reversal

Transcription

1 Now We Got Bad Blood: New Anticoagulant Reversal Kellie Rodriguez, PharmD, BCPS PGY2 Emergency Medicine Pharmacy Resident UF Health Jacksonville January 2016

2 Objectives 1. Review current treatment strategies for novel oral anticoagulant-induced major bleeding 2. Discuss antidote agents in the pipeline for reversal of novel oral anticoagulants

3 New Rx: Dabigatran 1 week later: AMS, HTN CT Head: Subarachnoid hemorrhage Patient Case 3

4 Novel oral anticoagulants (NOACs) Xa inhibitors Rivaroxaban Apixaban Edoxaban Direct thrombin inhibitor (DTI) Dabigatran 4

5 Pharmacokinetic properties Warfarin Rivaroxaban Apixaban Edoxaban Dabigatran Factor inhibition II, VII, IX, X Xa Xa Xa IIa Max concentration 4 h 2-4 h 3-4 h 1-2 h 1-3 h Bioavailability 100% % 50% 60% 5% Volume of distribution 10 L 50 L L 107 L L Protein binding 99% 92-95% 87% 55% 35% Renal clearance 92% 33% 27% 33% 80% Half life h 5-12 h 5-15 h h h Kaatz et al. Am. J. Hematol. 87:S141 S145, 2012.

6 NOAC effects on coagulation assays Xa inhibitors DTI aptt or or PT/INR or or TT ECT dtt/hemoclot * Antifactor Xa *, increase;, no change;, not applicable * Preferred test Siegal DM. Blood Feb 20;123(8): Garcia D. J Thromb Haemost Feb;11(2): aptt=activated partial prothrombin time; dtt=dilute thrombin time; ECT=ecarin clotting time; INR=international normalized ratio; PT=prothrombin time; TT=thrombin time 6

7 Treatment strategy approach Major bleeding Supportive care Blood product transfusion Agent-specific recommendations Xa inhibitors: 4-PCC Dabigatran: Hemodialysis apcc or 4-PCC Siegal et al. Blood Feb 20;123(8): PCC = four factor prothrombin complex concentrate apcc = activated prothrombin concentrate 7

8 Idarucizumab Recombinant humanized mouse antibody fragment Target: Dabigatran FDA-approved October 2015 Dabigatran 220 mg po bid x 3.5 days Phase 1 RCT, n=20 Assigned to 1 of 4 idarucizumab dose treatment arms Reversed all clotting parameters Mild adverse effects Glund S Aug 15;386(9994):

9 Design Prospective, phase 3 cohort study First 90 patients from trial Population Dabigatran-treated patients requiring urgent reversal Group A: Uncontrollable, life-threatening bleeding Group B: Urgent procedure Intervention Idarucizumab 5 g IV bolus Pollack CV. N Engl J Med Jun 22. [epub ahead of print]. 9

10 Results Primary endpoint Secondary endpoints Drug Concentrations Maximum percentage reversal: 100% ECT and dtt normalized 88-98% of patients Time to bleeding cessation: 11.4 h Idarucizumab: 4 h: by 80% from peak level Serious ADEs: n=21 Thrombotic events: n=5 Dabigatran (<20 ng/ml): 12 h: 93% 24 h: 79% Pollack CV. N Engl J Med Jun 22. [epub ahead of print]. dtt=dilute thrombin time ECT=ecarin clotting time 10

11 Andexanet alfa Factor Xa decoy Target: direct and indirect Xa-inhibitors Phase 3 trials ANNEXA-A (apixaban) ANNEXA-R (rivaroxaban) Lu Gl. Nature Medicine 2013;19(4): UFH = unfractionated heparin LMWH = low molecular weight heparin 11

12 ANNEXA-A and ANNEXA-R Primary outcome: % change anti-fxa Other findings 3.5 days Apixaban 5 mg po BID Healthy volunteers age 50-75, n=145 Rivaroxaban 20 mg po daily 4 days Andexanet alfa 400 mg IV bolus Andexanet alfa 400 mg IV bolus + 4 mg/min x 2 hr Andexanet alfa 800 mg IV bolus Andexanet alfa 800 mg IV bolus + 8 mg/min x 2 hr 94% vs. 21% p< % vs. 33% p< % vs. 18% p< % vs. 45% p< % anti-fxa in all patients Rapid restoration of thrombin generation (2-5 min) Rapidly reduced unbound [apixaban] & [rivaroxaban] (2-5 min) Siegal DM. N Engl J Med Nov 11.

13 Aripazine / PER977 Small molecular antibody Targets Xa-inhibitors, DTI, UFH and LWMH Binds through non-covalent hydrogen bonding and charge charge interactions Currently undergoing phase 2 studies Double-blind, placebo-controlled RCT in healthy patients (n=80) Edoxaban 60 mg po x1 PER or 300 mg IV x1 Whole-blood clotting time decreased to within 10% above the baseline value in 10 minutes Sustained effects >24 hours Mild adverse effects Ansell JE et al. N Engl J Med. 2014;371(22): DTI=direct thrombin inhibitor, LMWH=low molecular weight heparin UFH=unfractionated heparin 13

14 Reversal agents in the pipeline Dabigatran Idarucizumab Xa-inhibitors Andexanet alfa Universal Aripazine 14

15 Key Points Current treatment approach for new anticoagulant reversal includes 4-PCC for Xa-inhibitors and apcc or 4-PCC for dabigatran Idarucizumab is a newly approved antibody fragment for dabigatran reversal Other target specific agents in the pipeline include andexanet alfa for rivaroxaban and apixaban reversal and Aripazine as universal reversal agent

16 Now We Got Bad Blood: New Anticoagulant Reversal Kellie Rodriguez, PharmD, BCPS PGY2 Emergency Medicine Pharmacy Resident UF Health Jacksonville January 2016