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.

B.

Fresh frozen plasma 3-factor non-activated PCC C.

D.

E.

4-factor non-activated PCC Activated PCC (FEIBA) 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. 2012 Feb;141(2 Suppl). PMID: 22315259

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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. 2013 Sep 10;128(11): 1234-43. PMID: 2393511

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4 Factor PCC for Warfarin Related Bleeding

Sarode R. Circulation. 2013 Sep 10;128(11): 1234-43. PMID: 2393511

8

4 Factor PCC for Warfarin Related Bleeding

Sarode R. Circulation. 2013 Sep 10;128(11): 1234-43. PMID: 2393511

9

4 Factor PCC for Warfarin Related Bleeding

Sarode R. Circulation. 2013 Sep 10;128(11): 1234-43. PMID: 2393511

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 Company Boehringer Ingelheim Portola Pharmaceuticals, Inc.

Perosphere Inc.

Agent Idarucizumab:

Fully humanized Fab

Andexanet alfa:

Recombinant, modified human Factor Xa

Aripazine:

Di-arginine piperazine

Target

Dabigatran only Factor Xa Inhibitors (Riva; Apix; Edox) All NOACs (Dabi; Riva; Apix; Edox) UFH, LMWH, fondaparinux

Phase

III III 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 2014. https://ash.confex.com/ash/2014/webprogram/Paper74960.html

13

Idarucizumab

http://www.businesswire.com/news/home/20141209005097/en/data-show-specific-antidote-idarucizumab*-reverses-dabigatran-induced

14

Andexanet Alpha

https://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_469639.pdf

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Andexanet Alpha

https://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_469639.pdf

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Andexanet Alpha

https://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_469639.pdf

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PER977

Ansell JE. N Engl J Med. 2014 Nov 27;371(22):2141-2. PMID: 25371966

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PER977

Ansell JE. N Engl J Med. 2014 Nov 27;371(22):2141-2. PMID: 25371966

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.

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?

Observe and support B.

C.

Fresh frozen plasma 3- or 4-factor non-activated PCC D.

E.

Activated PCC (FEIBA) 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.

C.

D.

Ecarin clotting time E.

aPTT Dilute thrombin time Serum creatinine

22

Pharmacodynamics of TSOACs

Kaatz S. Am J Hematol. 2012 May;87 Suppl 1:S141-5. PMID: 22473649.

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

overdose may be considered.

to reduce absorption in case of XARELTO 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 apixaban blood levels.

activated charcoal

may be useful in the management of apixaban overdose or accidental ingestion by leading to a more rapid fall in 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. 2012 May;87 Suppl 1:S141-5. PMID: 22473649.

27

Dialysis and TSOACs

• • • • Dabigatran • Dabigatran is primarily eliminated by the kidneys with a low plasma protein binding of approximately 35%.

•

Hemodialysis

limited.

can remove dabigatran; however, data supporting this approach are • 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. 2013 Aug;36(2):195-202. PMID: 23657589.

30

Systematic Review of Factor VIIa RCTs

Levi M. N Engl J Med. 2010 Nov 4;363(19):1791-800. PMID: 21047223

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Systematic Review of Non-Activated PCC Cohort Studies

Dentali F. Thromb Haemost. 2011 Sep;106(3):429-38. PMID: 21800002

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. 2015 Jan 14. PMID: 25586208

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. 2013 Sep;34(36):2850-1. PMID: 23903774.

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