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Reversal of TSOACs
1st 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?• Fresh frozen plasma• 3-factor non-activated PCC• 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: 22315259Holbrook A. Chest. 2012 Feb;141(2 Suppl). PMID: 22315259
64 Factor PCC for
Warfarin Related Bleeding
Sarode R. Circulation. 2013 Sep 10;128(11): 1234-43. PMID: 2393511
74 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 DevelopmentReversal Agents in Development
Company Agent Target Phase
Boehringer-Ingelheim
Idarucizumab:Fully humanized
FabDabigatran 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 2014. https://ash.confex.com/ash/2014/webprogram/Paper74960.htmlGlund S. ASH December 2014. https://ash.confex.com/ash/2014/webprogram/Paper74960.html
13
http://www.businesswire.com/news/home/20141209005097/en/data-show-specific-antidote-idarucizumab*-reverses-dabigatran-induced
Idarucizumab
14
https://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_469639.pdf
Andexanet Alpha
15
https://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_469639.pdf
Andexanet Alpha
16
https://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_469639.pdf
Andexanet Alpha
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?• Observe and support• Fresh frozen plasma• 3- or 4-factor non-activated PCC• 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/INRB. aPTTC. Dilute thrombin timeD. Ecarin clotting timeE. Serum creatinine
22
Pharmacodynamics of TSOACs
Kaatz S. Am J Hematol. 2012 May;87 Suppl 1:S141-5. PMID: 22473649.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 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.comPradaxa.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.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 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.comPradaxa.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.
30Systematic Review of Factor VIIa RCTs
Levi M. N Engl J Med. 2010 Nov 4;363(19):1791-800. PMID: 21047223Levi M. N Engl J Med. 2010 Nov 4;363(19):1791-800. PMID: 21047223
31 Systematic Review of Non-Activated PCC Cohort Studies
Dentali F. Thromb Haemost. 2011 Sep;106(3):429-38. PMID: 21800002Dentali F. Thromb Haemost. 2011 Sep;106(3):429-38. PMID: 21800002
32FDA 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.comPradaxa.com, Xarelto.com, Eliquis.com, Savaysa.com
33
Siegal DM. J Thromb Thrombolysis. 2015 Jan 14. PMID: 25586208 Siegal DM. J Thromb Thrombolysis. 2015 Jan 14. PMID: 25586208
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 Camm AJ. Eur Heart J. 2013 Sep;34(36):2850-1. Sep;34(36):2850-1. PMID: 23903774. PMID: 23903774.