Reversal of TSOACs 1 st Qatar Conference on Safe Anticoagulation Management (QCSAM): New Advances and Trends 28 February 2015 Scott Kaatz, DO, MSc, FACP, FHM Chief Medical Officer Chief, Hospital Medicine Hurley Medical Center Clinical Associate Professor of Medicine Michigan State University

2 Full Disclosure Grant support Boehringer-Ingelheim Bristol Myer Squibb Bayer/Jansen/Johnson and Johnson Eisai Iverson Genetics Diagnostics/Medicare National Institute of Health Canadian Institute of Health Research Blue Cross/Blue Shield of Michigan Speaker honorarium Janssen Boehringer-Ingelheim Bristol Myer Squibb/Pfizer CSL Behring Consultant Boehringer Ingelheim Bristol Myer Squibb/Pfizer Janssen/Johnson and Johnson Daiichi Sankyo Board membership (non-profit) Thrombosis and Hemostasis Societies of North America AC Forum National Certification Board of Anticoagulation Providers National Blood Clot Alliance Medical and Scientific Advisory Board

Reversal of Target Specific Oral Anticoagulants (TSOACs)  Warfarin reversal  TSOAC antidotes in development  Treatment of TSOAC bleeding – Half-lives – Charcoal absorption – Dialysis – Prothrombotic agents – Guidance

4 Case 1 A 71-year-old female presents to the ER with hematochezia and on warfarin. INR 6.0; hemoglobin 6.0; BP low, pulse high In addition to vitamin K, what else should you give her? A.Fresh frozen plasma B.3-factor non-activated PCC C.4-factor non-activated PCC D.Activated PCC (FEIBA) E.rVIIa

5 ACCP Guidelines 9.3. For patients with VKA-associated major bleeding, we suggest rapid reversal of anticoagulation with four-factor prothrombin complex concentrate (PCC) rather than with plasma (Grade 2C). We suggest the additional use of vitamin K 5 to 10 mg administered by slow IV injection rather than reversal with coagulation factors alone (Grade 2C). Holbrook A. Chest Feb;141(2 Suppl). PMID:

6 4 Factor PCC for Warfarin Related Bleeding Question: Is 4-factor PCC as effective as FFP for hemostasis and INR correction in patients with warfarin-related bleeding? Design: open-label, non-inferiority RCT Patients: INR >2.0 with major bleeding Intervention: 4-factor non-activated PCC (Kcentra) Comparison: FFP Outcome: Hemostasis at 24 hours INR correction ½ hour after infusion finished Sarode R. Circulation Sep 10;128(11): PMID:

7 4 Factor PCC for Warfarin Related Bleeding Sarode R. Circulation Sep 10;128(11): PMID:

8 4 Factor PCC for Warfarin Related Bleeding Sarode R. Circulation Sep 10;128(11): PMID:

9 4 Factor PCC for Warfarin Related Bleeding Sarode R. Circulation Sep 10;128(11): PMID:

Reversal of Target Specific Oral Anticoagulants (TSOACs)  Warfarin reversal  TSOAC antidotes in development  Treatment of TSOAC bleeding – Half-lives – Charcoal absorption – Dialysis – Prothrombotic agents – Guidance

Reversal Agents in Development CompanyAgent Target Phase Boehringer- Ingelheim Idarucizumab: Fully humanized Fab Dabigatran only III Portola Pharmaceuticals, Inc. Andexanet alfa: Recombinant, modified human Factor Xa Factor Xa Inhibitors (Riva; Apix; Edox) III Perosphere Inc. Aripazine: Di-arginine piperazine All NOACs (Dabi; Riva; Apix; Edox) UFH, LMWH, fondaparinux II

12 Dabigatran Antibody Idarucizumab 46 male and female patients Dabigatran for 4 days (steady state) Idarucizumab 2 hours after dabigatran (peak) 5 mg completed corrected within 5 min Dilute thrombin time Ecarin clotting time aPTT Well tolerated and dabagitran redoes 24 hours later achieved anticoagulation effect Glund S. ASH December

13 Idarucizumab

14 Andexanet Alpha

15 Andexanet Alpha

16 Andexanet Alpha

17 Ansell JE. N Engl J Med Nov 27;371(22): PMID: PER977

18 PER977 Ansell JE. N Engl J Med Nov 27;371(22): PMID:

Reversal of Target Specific Oral Anticoagulants (TSOACs)  Warfarin reversal  TSOAC antidotes in development  Treatment of TSOAC bleeding – Half-lives – Charcoal absorption – Dialysis – Prothrombotic agents – Guidance

20 Case 2a A 71-year-old female presents to the ER with hematochezia and is on a TSOAC. Her hemoglobin dropped from 12.0 to 9.3 in 1 month. She is hemodynamically stable, renal function normal. Which is the best option? A.Observe and support B.Fresh frozen plasma C.3- or 4-factor non-activated PCC D.Activated PCC (FEIBA) E.rVIIa

21 Case 2b A 71-year-old female presents to the ER with hematochezia and is on a TSOAC. Her hemoglobin dropped from 12.0 to 9.3 in 1 month. She is hemodynamically stable. Which test is most useful to manage this patient? A.PT/INR B.aPTT C.Dilute thrombin time D.Ecarin clotting time E.Serum creatinine

22 Pharmacodynamics of TSOACs Kaatz S. Am J Hematol May;87 Suppl 1:S PMID:

Reversal of Target Specific Oral Anticoagulants (TSOACs)  Warfarin reversal  TSOAC antidotes in development  Treatment of TSOAC bleeding – Half-lives – Charcoal absorption – Dialysis – Prothrombotic agents – Guidance

24 Activated Charcoal and TSOACs Dabigatran Not mentioned Rivaroxaban The use of activated charcoal to reduce absorption in case of XARELTO overdose may be considered. Apixaban In healthy subjects, administration of activated charcoal 2 and 6 hours after ingestion of a 20-mg dose of apixaban reduced mean apixaban AUC by 50% and 27%, respectively. Mean apparent half-life of apixaban decreased from 13.4 hours when apixaban was administered alone to 5.3 hours and 4.9 hours, respectively, when activated charcoal was administered 2 and 6 hours after apixaban, indicating that charcoal blocked the continued absorption of apixaban from the gut [see Clinical Pharmacology (12.3)]. Thus, administration of activated charcoal may be useful in the management of apixaban overdose or accidental ingestion by leading to a more rapid fall in apixaban blood levels. Edoxan Not mentioned Pradaxa.com, Xarelto.com, Eliquis.com, Savaysa.com

Reversal of Target Specific Oral Anticoagulants (TSOACs)  Warfarin reversal  TSOAC antidotes in development  Treatment of TSOAC bleeding – Half-lives – Charcoal absorption – Dialysis – Prothrombotic agents – Guidance

26 Pharmacodynamics of TSOACs Kaatz S. Am J Hematol May;87 Suppl 1:S PMID:

27 Dialysis and TSOACs Dabigatran Dabigatran is primarily eliminated by the kidneys with a low plasma protein binding of approximately 35%. Hemodialysis can remove dabigatran; however, data supporting this approach are limited. Using a high-flux dialyzer, blood flow rate of 200 mL/min, and dialysate flow rate of 700 mL/min, approximately 49% of total dabigatran can be cleared from plasma over 4 hours. At the same dialysate flow rate, approximately 57% can be cleared using a dialyzer blood flow rate of 300 mL/min, with no appreciable increase in clearance observed at higher blood flow rates. Upon cessation of hemodialysis, a redistribution effect of approximately 7% to 15% is seen. The effect of dialysis on dabigatran’s plasma concentration would be expected to vary based on patient specific characteristics. Measurement of aPTT or ECT may help guide therapy Rivaroxaban Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable Apixaban Because of high plasma protein binding, apixaban is not expected to be dialyzable Edoxaban Hemodialysis does not significantly contribute to edoxaban clearance Pradaxa.com, Xarelto.com, Eliquis.com, Savaysa.com

Reversal of Target Specific Oral Anticoagulants (TSOACs)  Warfarin reversal  TSOAC antidotes in development  Treatment of TSOAC bleeding – Half-lives – Charcoal absorption – Dialysis – Prothrombotic agents – Guidance

29 Composition of PCCs Kaatz S, Crowther M. J Thromb Thrombolysis Aug;36(2): PMID:

30 Systematic Review of Factor VIIa RCTs Levi M. N Engl J Med Nov 4;363(19): PMID:

31 Systematic Review of Non-Activated PCC Cohort Studies Dentali F. Thromb Haemost Sep;106(3): PMID:

32 FDA Labeling Dabigatran Activated prothrombin complex concentrates (aPCCs, e.g., FEIBA), or recombinant Factor VIIa, or concentrates of coagulation factors II, IX or X may be considered but their use has not been evaluated in clinical trials. Rivaroxaban Partial reversal of prothrombin time prolongation has been seen after administration of prothrombin complex concentrates (PCCs) in healthy volunteers. The use of other procoagulant reversal agents like activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (rFVIIa) has not been evaluated. Apixaban Use of procoagulant reversal agents such as prothrombin complex concentrate, activated prothrombin complex concentrate, or recombinant factor VIIa may be considered but has not been evaluated in clinical studies. Edoxaban A specific reversal agent for edoxaban is not available. Hemodialysis does not significantly contribute to edoxaban clearance [see Clinical Pharmacology (12.3)]. Protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse the anticoagulant activity of SAVAYSA. Pradaxa.com, Xarelto.com, Eliquis.com, Savaysa.com

33 Siegal DM. J Thromb Thrombolysis Jan 14. PMID:

34

Reversal of Target Specific Oral Anticoagulants (TSOACs)  Warfarin reversal  TSOAC antidotes in development  Treatment of TSOAC bleeding – Half-lives – Charcoal absorption – Dialysis – Prothrombotic agents – Guidance

36 Reversal of TSOACs Camm AJ. Eur Heart J Sep;34(36): PMID:

Reversal of Target Specific Oral Anticoagulants (TSOACs)  Warfarin reversal  TSOAC antidotes in development  Treatment of TSOAC bleeding – Half-lives – Charcoal absorption – Dialysis – Prothrombotic agents – Guidance