1. Management of Bleeding on Factor Xa Inhibitor Therapy – Does One Size Fit All?
Nubriel Hernandez, PharmD
PGY-1 Pharmacy Resident
SUNY Downstate Medical Center
Brooklyn, NY

2. Disclosure
I have no conflict of interest to report and I intend to reference unlabeled/unapproved uses of drugs or products in my presentation

3. Objectives
Recognize current management strategies for patients who present with major bleeding episodes while on oral anticoagulation
Understand the limitations of current strategies of factor Xa inhibition reversal

4. Oral Anticoagulants
Warfarin was the first anticoagulant approved in 1954
Due to limitations of warfarin, new oral anticoagulants have been approved
Novel anticoagulants: direct thrombin inhibitors and factor Xa inhibitors
Yang J, et. al. Eur J Med Chem. 2015;101:

5. Major Bleeding Rates for Factor Xa Inhibitors
Bleeding Event Rates Per Year vs. Warfarin
Rivaroxaban
Warfarin
Apixaban
Edoxaban
3.6%
3.4%
2.13%
3.09%
2.75%
3.43%
p=0.58
p<0.001
Rates are for NVAF. Major bleeding defined as intracranial bleeding, bleeding requiring hospitalization, a Hgb decrease of more than 2 g/dL or the need for transfusion secondary to bleeding.
Major Bleeding vs. Warfarin
Betrixaban
Warfarin
2.4% (3/127)
3.9% (5/127)
HR (95% CI): ( )
Connolly SJ, et. Al. Eur Heart J. 2013;34(20):
Eikelboom J et al. Am J Emerg Med. 2016;34(11S):3-8.

6. Pharmacokinetic Parameters
Medication
Rivaroxaban (Xarelto®)
Apixaban
(Eliquis®)
Edoxaban
(Savaysa®)
Betrixaban
(Bevyxxa®)
Onset of Action (hr)
2 to 4
3 to 4
1 to 2
Metabolism
Hepatic
CYP 3A4/5, 2J2, PGP substrate
CYP 3A4/5, 1A2, 2C8, 2C9, 2C19, 2J2, PGP substrate
Minimal via CYP 3A4
PGP and ABCB1 substrate
Protein Binding (%)
~92 to 95
~87
~55 60
T1/2 (hr)
5 to 9
8 to 15
10 to 14
19 to 27
Excretion (%)
Urine: 66
Urine: 27
Urine: 50
Urine: 11
Bevyxxa fecal excretion ~85%. FDA approved for DVT prophylaxis inpatient only.
BEVYXXA is indicated for the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE for a total of 35 to 42 days
PGP: P-glycoprotein; CYP: Cytochrome P450; ABCB1: ATP Binding Cassette Subfamily B Member 1
Lexicomp Online®, Lexi-Drugs®, Hudson, Ohio: Lexi-Comp, Inc.

7. Management of Factor Xa Toxicity
Activated Charcoal
Within 2-4 hours of exposure
Dose: 50 g x1 dose
4 Factor Prothrombin Complex Concentrates (4F-PCC) or activated Prothrombin Complex Concentrates (aPCC)
Fresh Frozen Plasma (FFP) last line option?
Assessment of laboratory markers and symptoms of bleeding
Hemodialysis ineffective
Activated charcoal has been shown to decrease rivaroxaban up to 8 hours post exposure by 29%.
Dabigatran's effect may best be quantified with dilute TT and ecarin-based assays, but these tests are not widely available and are not standardized between laboratories; a normal aPTT or normal TT rules out significant levels of dabigatran. Among the factor Xa inhibitors, rivaroxaban and apixaban require an anti-Xa activity assay calibrated to the specific drug itself. A normal PT/INR excludes significant levels of rivaroxaban, but not apixaban. Edoxaban may be reliably measured with an anti-FXa assay calibrated to heparin or edoxaban. Thus, the standard coagulation assays may be of some utility when over- or under-dosing is suspected, but their ability to quantify drug effect is limited.
Tomaselli GF, et. al. J Am Coll Cardiol. 2017;70(24):

8. Role of Factor Replacement
Gulseth MP. Am J Health Syst Pharm. 2016;73(10 Suppl 2):S5-S13.

9. Prothrombin Complex Concentrates (PCCs)*
3 factor PCCs (Bebulin® or Profilnine®)
4 factor PCCs (Kcentra®); 50 Units/kg IV (Max: 5,000 Units)
Activated PCCs (FEIBA®); 50 – 100 Units/kg IV
Differ in presence of factor VII
Contraindicated:
Active disseminated intravascular coagulopathy
Recent history of heparin-induced thrombocytopenia (HIT)
4FPCC contains comparable physiologic Factor VII making it the distinguishing factor along with antithrombotic proteins C and S. Comparison shows less adequate INR reversal with 3FPCC vs 4FPCC
Warfarin dosing: INR 2-4: 25 U/kg
INR 4-6: 35 U/kg
INR >6: 50 U/kg
1000 Units for major bleed
1500 Units for intracranial hemorrhage
Benefits of PCC
include its fast preparation and reconstitution time, rapid
INR reversal, small volume, and lower risk of infection as
compared to FFP
Daily max of aPCC is 200 U/kg; Anti-inhibitor coagulant complex, also known as activated prothrombin complex concentrate (APCC) is a preparation containing precursor and activated forms of blood coagulation factors II, VII, IX, and X derived from pooled human venous plasma. FEIBA contains mainly non-activated factors II, IX, and X and mainly activated factor VII. It contains
approximately equal unitages of factor VIII inhibitor bypassing activity and prothrombin complex
factors. In addition, the preparation contains 1-6 units of factor VIII coagulant antigen (FVIII C:Ag) per
mL. The product contains traces of factors of the kinin generating system.
* These products are not FDA-indicated for reversal of bleeding with exposure to Factor Xa Inhibitors
Tomaselli GF, et. al. J Am Coll Cardiol. 2017;70(24):

10. Fresh Frozen Plasma Obtained from whole blood donation
1 Unit = mL
Requires ABO blood type matching and thawing
May take up to 90 minutes from time of order to time of administration
Tomaselli GF, et. al. J Am Coll Cardiol. 2017;70(24):

11. FFP vs 4F-PCC Category FFP 4F-PCC Infection Rates  
Increased Intravascular Volume

Anaphylaxis
Speed of INR Correction
~6 hrs
~10 mins
Coagulation Factors
All
II, VII, IX and X
Costs $$
$$$
Lexicomp Online®, Lexi-Drugs®, Hudson, Ohio: Lexi-Comp, Inc.
Tomaselli GF, et. al. J Am Coll Cardiol. 2017;70(24):

12. Guideline Recommendations: Warfarin
4F-PCC based on patient’s weight and INR
Fixed low dose regimen of 4F-PCC
INR 2-4:
25 Units/kg
INR 4-6:
50 Units/kg
INR 2-4:
25 Units/kg
1,000 Units (non-major bleed)
1,500 Units (Intracranial Hemorrhage)
* If 4F-PCC is not available: FFP mL/kg
Tomaselli GF, et. al. J Am Coll Cardiol. 2017;70(24):

13. Guideline Recommendations
Factor Xa Inhibitors
4F-PCC: 50 Units/kg
aPCC: 50 Units/kg
Tomaselli GF, et. al. J Am Coll Cardiol. 2017;70(24):

14. Literature Review Study Design Number Population Intervention Outcome
Klein L, Peters J, Miner J, Gorlin J. Evaluation of fixed dose 4-factor prothrombin complex concentrate for emergent warfarin reversal. Am J Emerg Med. 2015;33(9):
Study Design
Retrospective cohort study
Number
38 subjects on chronic oral anticoagulation with warfarin;
1 subject on chronic oral anticoagulation with rivaroxaban
Population
Patients admitted to urban level I trauma center in MN from March 2014 to January 2015
Intervention
4F-PCC 1,500 Units x1 dose; additional dose if deemed necessary (median dose 1659 Units)
Outcome
36 patients (92.3%) had a successful INR reversal with target less than 2.0 and 28 patients (71.8%) had a successful INR reversal with target of 1.5 or less
No thrombotic events reported within 7 days
KCENTRA used study done in MN, USA

15. Literature Review
Klein L, et.al. Am J Emerg Med. 2015;33(9):

16. Literature Review Study Design Number Population Intervention Outcome
Zahir H, Brown KS, Vandell AG, et al. Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation. 2015;131(1):82-90.
Study Design
Phase I, double-blind, randomized, placebo-controlled, 2-way crossover study
Number
110 subjects; Part 1: 17 subjects and Part 2: 93 subjects
Population
Healthy men and women, aged 18 to 45 years, weighing ≤ 110 kg were eligible for study enrollment. All patients received edoxaban 60 mg by mouth
Intervention
4F-PCC in decreasing dosing increments (50, 25 and 10 Units/kg) or placebo
Outcome
Average of 21% decrease in baseline normalized post-dose bleeding duration following administration of 50 Units/kg of 4F-PCC (mean ratio 4F-PCC versus placebo, 79.2; 95% CI, 61.5 – 101.9; p= 0.068)
Complete reversal was observed following 4F-PCC dose of 50 Units/kg, partial reversal following 25 Units/kg and no reversal following 10 Units/kg
No deaths, serious adverse events, or thromboembolic events occurred
KCENTRA used study done in MN, USA

17. Literature Review Study Design Number Population Intervention Outcome
Majeed A, Ågren A, Holmström M, et al. Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study. Blood. 2017;130(15):
Study Design
Prospective cohort study
Number
84 subjects; 39 were on apixaban and 45 were on rivaroxaban
Population
Patients requiring treatment with 4F-PCC who presented with a major bleeding event defined by the International Society of Thrombosis and Hemostasis (ISTH)
Intervention
4F-PCC given as fixed dose dependent on weight:
< 65 kg = 1,500 IU, > 65 kg = 2,000 IU
Outcome
Hemostatic effectiveness in 58 patients (69.1%) and ineffective in 26 patients (30.9%)
27 patients (32%) died within 30 days of major bleeding event, of which 20 had an intracranial hemorrhage
PCCs were given at a median dose of 2000 Units, suggesting this dose may be adequate in patients who present with a major bleeding event
Confidex and Ocplex used in this study

18. Summary
One size does not fit all – limited data to suggest that similar benefits exist for factor Xa inhibitors using fixed dose 4F-PCC
FFP has greater disadvantages associated with its use as a reversal agent compared to 4F-PCC
Acute ingestion – Consider activated charcoal if time of ingestion is known, symptom management and watch for signs of bleeding

19. Test Your Knowledge

20. Test Your Knowledge
Which strategies could be considered in a patient for Factor Xa reversal?
Hemodialysis
4F-PCC given at a dose of 50 IU/kg
4F-PCC given at a dose of 10 IU/kg
aPCC given at a dose of 50 IU/kg
B and D

21. Test Your Knowledge
What are current limiting factors in managing patients who present with bleeding while on Factor Xa Inhibitor Therapy?
Lack of specific reversal agent availability
Limited data of 4F-PCC use in bleeding patients
Limited availability and/or utility of laboratory markers
All of the above

22. References
Yang J, Su G, Ren Y, Chen Y. Synthesis of 3,4-diaminobenzoyl derivatives as factor Xa inhibitors. Eur J Med Chem. 2015;101: Lexicomp Online® , Lexi-Drugs® , Hudson, Ohio: Lexi-Comp, Inc.; accessed January 21, Tomaselli GF, Mahaffey KW, Cuker A, et al ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2017;70(24): Levi M, Moore KT, Castillejos CF, et al. Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers. J Thromb Haemost. 2014;12(9): Zahir H, Brown KS, Vandell AG, et al. Edoxaban effects on bleeding following punch biopsy and reversal by a 4- factor prothrombin complex concentrate. Circulation. 2015;131(1): Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124(14): Gulseth MP. Overview of direct oral anticoagulant therapy reversal. Am J Health Syst Pharm. 2016;73(10 Suppl 2):S5-S13. Eikelboom J, Merli G. Bleeding with direct oral anticoagulants vs warfarin: clinical experience. Am J Emerg Med. 2016;34(11S):3-8.

23. References, Continued
Majeed A, Ågren A, Holmström M, et al. Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study. Blood. 2017;130(15): Tellor KB, Barasch NS, Lee BM. Clinical experience reversing factor Xa inhibitors with four-factor prothrombin complex concentrate in a community hospital. Blood Transfus. 2017; 1-5. Connolly SJ, Eikelboom J, Dorian P, et al. Betrixaban compared with warfarin in patients with atrial fibrillation: results of a phase 2, randomized, dose-ranging study (Explore-Xa). Eur Heart J. 2013;34(20): Klein L, Peters J, Miner J, Gorlin J. Evaluation of fixed dose 4-factor prothrombin complex concentrate for emergent warfarin reversal. Am J Emerg Med. 2015;33(9): Khorsand N, Veeger NJ, Muller M, et al. Fixed versus variable dose of prothrombin complex concentrate for counteracting vitamin K antagonist therapy. Transfus Med. 2011;21(2): Wang X, Mondal S, Wang J, et al. Effect of activated charcoal on apixaban pharmacokinetics in healthy subjects. Am J Cardiovasc Drugs. 2014;14(2): Yeh CH, Fredenburgh JC, Weitz JI. Oral direct factor Xa inhibitors. Circ Res. 2012;111(8): Joseph R, Burner J, Yates S, Strickland A, Tharpe W, Sarode R. Thromboembolic outcomes after use of a four-factor prothrombin complex concentrate for vitamin K antagonist reversal in a real-world setting. Transfusion. 2016;56(4):

24. Questions
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