1. Through Thick and Thin: approaches to anticoagulant Reversal
Jason Williamson, PharmD, BCPS
Clinical Pharmacy Specialist – Drug Use Policy and Education
Genesys Regional Medical Center
Through Thick and Thin: approaches to anticoagulant Reversal
The speaker has no actual or potential Conflict of Interest in relation to this presentation.

2. Objectives - Pharmacist
Given a patient case, identify the appropriate dosing regimen of a reversal agent or factor product utilized to reverse the effects of a direct-acting oral anticoagulant (DOAC).
Given a patient case, select appropriate monitoring parameters after the utilization of a reversal agent or factor product for the reversal of a DOAC.
Discuss the benefits of blood factor/anticoagulant reversal agent stewardship programs on patient care and on health care expenditures.

3. Objectives – Pharmacy Technician
Distinguish between reversal agents and factor products utilized in DOAC reversal.
Select appropriate steps in the administration of idarucizumab for the reversal of dabigatran.
Identify adverse effects associated with available reversal agents and factor products.

4. Audience Polling Question
Which of the following best describes your experience with blood factor products and anticoagulant reversal agents?
I have extensive experience with blood factor products and anticoagulant reversal agents (e.g., involved in everyday practice)
I have some experience with blood factor products and anticoagulant reversal agents (e.g., involved with a case requiring a blood factor or reversal agent every so often)
I have minimal to no experience with blood factor products and anticoagulant reversal agents (e.g., very few cases in practice, I usually hand off to another pharmacist)
I have some experience with these medications but have great difficulty keeping up with the rapid changes in evidence-based reversal strategies

5. Strategies for Reversal of Direct-Acting Oral Anticoagulants

6. Direct Acting Oral Anticoagulants (DOAC’s)
Includes four unique agents that were developed to improve upon the shortcomings of warfarin
Apixaban (Eliquis)
Dabigatran (Pradaxa)
Edoxaban (Savaysa)
Rivaroxaban (Xarelto)
Despite some improvements to these shortcomings (e.g., lack of dietary concerns with use, relatively fewer drug interactions, etc), an issue with the use of DOAC’s arose
Lack of specific reversal agent/antidote (until recently)
How do practitioners manage bleeding episodes associated with the DOAC’s?
How to practitioners manage patients treated with a DOAC who require an emergency surgery/urgent procedure?

7. Direct-Acting Oral Anticoagulants as a Class – Indications and PK/PD
Characteristic
Apixaban
Dabigatran
Edoxaban
Rivaroxaban
Indications
NVAF
DVT/PE treatment
DVT/PE prophylaxis after TKA/THA
DVT/PE prophylaxis after THA
Renal elimination of unchanged drug (%) 27 80 50 36
Half-life (hr)
8-15
12-14
10-14
5-9
Protein binding (%) 87 35 55
92-95
Dialyzable?
Unlikely
Yes

8. Selected Direct-Acting Oral Anticoagulants–
Major Bleeding and GI Bleeding
Drug
Endpoint
Major Bleeding
GI Bleeding
Apixaban vs warfarin
Prevention of stroke or systemic embolism in patients with NVAF
2.13% vs 3.09%
0.76% vs 0.86%
Dabigatran vs warfarin
Prevention of stroke or systemic embolism with NVAF
3.11% vs 3.36%
1.51% vs 1.02%
Prevention of recurrent VTE in patients with acute VTE
1.6% vs 1.9%
4.2% vs 2.8%
Rivaroxaban vs warfarin
Prevention of stroke and systemic embolism in patients with NVAF
3.6% vs 3.4%
No data
Prevention of recurrent VTE in patients with PE
1.1% vs 2.2%

9. Selected Direct-Acting Oral Anticoagulants –
Intracranial Hemorrhage and Fatal Bleeding
Drug
Endpoint
Intracranial Hemorrhage
Fatal Bleeding
Apixaban vs warfarin
Prevention of stroke or systemic embolism in patients with NVAF
0.33% vs 0.8%
No data
Dabigatran vs warfarin
Prevention of stroke or systemic embolism with NVAF
0.3% vs 0.74%
1.45% vs 1.8%
Prevention of recurrent VTE in patients with acute VTE
0% vs 0.2%
0.08% vs 0.08%
Rivaroxaban vs warfarin
Prevention of stroke and systemic embolism in patients with NVAF
0.5% vs 0.7%
0.2% vs 0.5%
Prevention of recurrent VTE in patients with PE
<0.1% vs 0.4%
<0.1% vs 0.1%

10. Coagulation assays and DOAC’s
Routine monitoring of coagulation assays is typically not required for the DOAC’s
Extenuating Circumstances
Major bleeding
Surgery
Reversal of anticoagulation
Suspicion of overdose

11. Coagulation Assays aPTT Chromogenic Anti-factor Xa
Intrinsic pathway
Chromogenic Anti-factor Xa
Functional test which assesses plasma factor Xa concentrations
Ecarin clotting time (ECT)
Specific assay for thrombin production
Direct measure of direct thrombin inhibitor activity (e.g., dabigatran)
PT-INR
Extrinsic and common pathway
Thrombin clotting time (TT)
Directly assesses activity of thrombin

12. Usefulness of Coagulation Assays
Factor IIa inhibitors (e.g., dabigatran)
ECT > TT > aPTT > PT/INR
Factor Xa inhibitors (e.g., apixaban, edoxaban, rivaroxaban)
Chromogenic anti-factor Xa > PT/INR > aPTT
Despite these depictions of the optimal coagulation assays for each type of DOAC, many health systems lack an ability to utilize these tests or have to send out specimens for analysis by another laboratory

13. Non-pharmacologic Management of Bleeding
Discontinue the anticoagulant involved
Target hemostasis at the bleeding site
Fluid resuscitation/hemodynamic support
Transfusion
Further intervention with factor products/reversal agents is often required

14. Pharmacologic Management of Bleeding
Activated charcoal
May be effective if given within 1-2 hours of last DOAC dose
Hemodialysis
May be considered in patients treated with dabigatran due to low plasma protein binding
May decrease drug levels by at least 50% after a 4 hour session
Multiple factor products may be used for DOAC reversal
Hospital formulary restrictions typically play a factor in which factor products are selected for use
Thromb Haemost. 2013;109:

15. Selected Factor Products
3 Factor PCC
4 Factor PCC
Brand Name
Bebulin VH
Profilnine SD
Kcentra
Dose based on
Units of factor IX activity
Factor II
24-38 IU/mL
150IU/100 fIX IU
units/unit
Factor VII
< 5 IU/mL*
< 35 IU/100 fIX IU*
0.4-1 unit/unit
Factor IX
100 IU
units/unit
Factor X
100 IU/100 fIX IU
units/unit
Unfractionated heparin
0.15 IU per 1 IU fIX
None
unit/unit
Other components -
Protein C, Protein S, Anti-thrombin III
* denotes products with non-therapeutic levels of factor VII

16. Selected Factor Products
aPCC
rFVIIa
Brand Name
Feiba NF
NovoSeven RT
Dose based on
Units of factor VIII inhibitor bypassing activity
Units of recombinant factor VIIa
Factor II
1.3 IU/IU -
Factor VII
0.9 IU/IU X
mcg X
Factor IX
1.4 IU/IU
Factor X
1.1 IU/IU
Unfractionated heparin
None
Other components
X denotes products with activated factor VII

17. Thrombogenicity Associated with Factor Product Administration
Use of factor products as part of a patient-specific DOAC reversal strategy may confer an increased risk of a pro-thrombotic state
Specific factor component involvement has not been clearly defined
Products containing protein C, protein S, and other anticoagulants may preclude excessive thrombin production
Providers must carefully balance the benefits of anticoagulant reversal with the risks of thrombosis after reversal or seek alternate methods of reversal
“Targeted anti-anticoagulants” or agent-specific antidotes offer less risk for thrombogenicity than factor product counterparts

18. Idarucizumab (Praxbind)
Approved in October 2015 for the reversal of the anticoagulant effects of dabigatran for emergency surgery/urgent procedures or in life-threatening or uncontrolled bleeding
Mechanism of action: humanized monoclonal antibody fragment that binds to dabigatran and its acylglucuronide metabolites with an affinity for dabigatran ~ 350 times greater than thrombin

19. Idarucizumab Dosing and administration
5 gm IV (given as 2 separate 2.5 gm doses no more than 15 minutes apart)
May be given as IV push or as IV infusion
Give within 1 hour of removing from the vial if IV push selected
Infuse no longer than 5 to 10 minutes if IV infusion selected
No reconstitution required
If specific coagulation parameters are re-elevated and clinically relevant bleeding occurs OR if a second emergency surgery/urgent procedure is needed and the patient elevated coagulation parameters, an additional 5 gm dose may be considered (supported by limited data)

20. Idarucizumab PK/PD
In general, this agent neutralizes the anticoagulant effects of idarucizumab within minutes of administration
Median time of hemostasis restoration = 11.4 hours
Duration of at least 24 hours
Half-life elimination 47 minutes (initial); 10.3 hours (terminal)
Metabolized to small peptides and amino acids; also excreted in the urine

21. Idarucizumab storage/stability
Store intact vials at 36 – 46oF; do not freeze
Do not shake; do not tube (monoclonal antibody)
Can be stored in original packaging at room temperature
Up to 48 hours if in original packaging (protected from light)
Up to 6 hours if exposed to light

22. Warnings/Precautions with Idarucizumab
Coagulation parameter re-elevation may occur in some patients (limited number in clinical trials). If clinically relevant bleeding occurs in conjunction with elevated coagulation parameters, consider an additional dose of idarucizumab.
Hypersensitivity may occur from administration
Due to the underlying risk of thromboembolism associated with reversed the effects of dabigatran, labeled dosing information recommends restarting dabigatran or an alternative anticoagulant when appropriate.
Hereditary fructose intolerance?

23. Evidence from REVERSE-AD Trial
Purpose: determine the safety of 5 gm IV idarucizumab and its capacity to reverse the anticoagulant effects of dabigatran in patients who had a serious bleed or required an urgent procedure
Primary endpoint: maximum percentage reversal of dabigatran within 4 hours after administration of idarucizumab
Pre-dose test result [s]–minimum post-dose test result [s])
(Pre-dose test result [s]–upper limit of the normal range [s])×100
Secondary endpoint: restoration of hemostasis
N Engl J Med. 2015;373(6):

24. Evidence from REVERSE-AD Trial
Idarucizumab rapidly and completely reversed the anticoagulant activity of dabigatran in 88% to 98% of patients with elevated clotting times at baseline
There were no safety concerns among the 90 patients involved in this study
Includes patients given idarucizumab on clinical grounds but were later found to have had normal results on clotting tests at baseline
N Engl J Med. 2015;373(6):

25. In the Pipeline: andexanet Alfa
Presently studied but not yet approved for factor Xa inhibitor reversal (e.g., rivaroxaban, apixaban, edoxaban, fondaparinux)
Currently being studied in phase 4 trials (ANNEXA-4), and phase 3 trials (ANNEXA-A and ANNEXA-R) were released in 2015
Purported mechanism of action: recombinant modified human factor Xa decoy protein that is catalytically inactive but retains the ability to bind factor Xa inhibitors in the active state at a high affinity, restoring the activity of endogenous factor Xa

26. Evidence from ANNEXA-A and ANNEXA-R Trials
Phase III, randomized, double-blind, placebo-controlled clinical trials from March 2014 – May 2015 involving 2 clinical sites
Inclusion criteria – age 50 – 75 years
Exclusion criteria – history of:
Abnormal bleeding, active bleeding, or risk factors for bleeding
Thrombosis or risk factors for thrombosis
Adult asthma or use of inhaled medication
Primary study endpoint: percent change in anti-factor Xa activity (examined nadir associated with bolus and with infusion)
N Engl J Med. 2015;373(25):

27. Evidence from ANNEXA-A and ANNEXA-R Trials
Percent change in anti-factor Xa activity (mean  SD)
Study
Andexanet
Placebo
P-value
Bolus
ANNEXA-A
942%
219%
< 0.001
ANNEXA-R
9211%
1815%
Bolus + Infusion
923%
336%
972%
4512%
N Engl J Med. 2015;373(25):

28. Other Reversal Agents in the Pipeline
Aripazine (PER977; ciraparantag) – reversal of all DOAC’s presently on the market
May additionally work against heparin and LMWH
N Engl J Med. 2014;371(22):

29. Strategies for Reversal of warfarin

30. Advances In the Management of Warfarin Reversal
Phytonadione (vitamin K) is the antidote to warfarin, but this agent by itself may not be sufficient for acute major bleeding issues or where rapid reversal of anticoagulation prior to an emergency surgery is required
Four factor prothrombin complex concentrate (Kcentra) is now approved for the reversal of warfarin in specific patients

31. Prothrombin Complex Concentrate (Kcentra)
Contains factors II, VII, IX, and X as well as protein C and S (a.k.a. 4 factor PCC)
Indicated for the urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist (e.g., warfarin) therapy in patients with acute major bleeding or a need for an urgent surgery/invasive procedure
Dose depends on pretreatment INR and on patient weight

32. Dosing 4 Factor PCC Pre-treatment INR 2 - < 4 4 – 6 > 6
Dose (units of factor IX)/ kg body weight 25 35 50
Maximum dose (units of factor IX)
Not to exceed 2500
Not to exceed 3500
Not to exceed 5000
Dose based on actual potency as stated on the carton, which varies from factor IX units/mL after reconstitution. Nominal potency is 500 units or 1000 units per vial (25 units/mL after reconstitution).

33. Notable Warnings/Precautions with 4 Factor PCC
Increased risk for thromboembolic events (Boxed Warning in the US)
As patients treated with vitamin K antagonists have an underlying risk of or a diagnosed thromboembolic disease state, administration of PCC may predispose the patient to a thromboembolic complication
Formulations contain heparin and are products or human plasma (may contain infectious agents)
4 factor PCC products contain factor VII ad should not be confused with other products that contain low or nontherapeutic levels of factor VII (e.g., Profilnine)
Hypersensitivity reactions may occur from administration

34. Evidence for 4 Factor PCC Products
Numerous prospective interventional trials and retrospective observational studies have been published supporting use
Notable publications
Sarode et al. Circulation. 2013;128(11):
Pabinger et al. Journal of Thrombosis and Haemostasis. 2008;6(4):
Preston et al. British Journal of Haematology. 2002;116(3):
Open-label, randomized, multicenter phase III soon to be published comparing 4 factor PCC to plasma in patients requiring urgent surgery (N = 176)

35. Factor product/ reversal agent Stewardship Programs

36. Stewardship Program for factor products/reversal agents
University of North Carolina Medical Center (UNCMC)
Innovative pharmacist-led program to improve prescribing, dosing, and monitoring of clotting factor therapy
Pharmacist assigned to round with hematologists daily, recommending treatment plan modifications and dose adjustments as necessary
Am J Health Syst Pharm. 2015;72(18):

37. Steps to Program development/implementation
Selection of one formulary product within each clotting factor class
Establishment of guidelines on blood factor prescribing, order review, compounding, and administration
Initial and ongoing education of pharmacy, nursing, and medical staff
Am J Health Syst Pharm. 2015;72(18):

38. Results of UNCMC Program
Contributed both to cost savings and improved outcomes
Increase in patients receiving clotting factors by 22%, but reduction of doses dispensed by 45% overall
Reduction in readmissions associated with bleeding episodes for patients with hemophilia A
Cost-savings estimated to exceed $4 million annually (from 4 year program period)
Numerous opportunities for improvement contributed to reduction of doses dispensed
Conversion of patients with hemophilia A or B from intermittent infusions of factors VIII and IX to continuous infusion therapy
Change in product selection for patients with hemophilia A
Review of factor concentrate doses ordered beyond initial dose by designated pharmacist team member
Am J Health Syst Pharm. 2015;72(18):

39. Applying this Article to Anticoagulation Reversal
Despite many specific roles with blood factor use with inherited bleeding disorders, a designated team of pharmacists could be formed to optimize the utilization of blood factor and reversal agent products within a variety of health systems
Specific institutional guidelines should be developed and utilized to guide factor product and reversal agent selection, dosing, and subsequent monitoring
An interdisciplinary approach would likely result in the greatest improvements in patient care as well as cost savings

40. design for factor product/reversal agent stewardship
Pharmacist Chair and Physician Chair
Support Pharmacists
Drug Use Policy/
Formulary Management
Pharmacy and Health System Administration

41. Conclusions
A variety of factor products and reversal agents (e.g., agent specific antidotes) are available or in the pipeline for the reversal of anticoagulation
Pharmacy staff members can assist with vital roles associated with the use, dosing, administration, and patient monitoring of medications used in anticoagulant reversal
Factor and reversal agent stewardship programs have the potential to improve patient care as well as contain health care costs

42. Discussion/Questions

43. Patient Case - Pharmacist
Patient LK presents to the MICU with a new onset GI bleed. Upon reviewing the patient’s medication profile, you discover that the home medication list includes multiple blood thinners. Among these blood thinners, dabigatran 150 mg PO BID was prescribed for this patient for their NVAF. The patient weighs 89 kg, is 87 years old, and is presently receiving hemodialysis for their end stage renal disease. Hematology/oncology is consulted and decides to hold anticoagulation and initiate idarucizumab for reversal. As the pharmacist, hem/onc seeks your input for this patient’s care about the overall reversal strategy.

44. Question 1 - Pharmacist
What’s the most appropriate dosing regimen of idarucizumab to utilize for this patient case?
2.5 gm IV push X 2 doses (no more than 15 minutes apart)
5 gm IV push X 1 dose
2.5 gm as an IV infusion X 2 doses
A and C

45. Question 2 - pharmacist
During administration of the idarucizumab, the prescribing physician wants your suggestions about further monitoring of the patient. What information do you provide the physician?
There is no further monitoring required.
Monitor for re-elevation of coagulation parameters (e.g., aPTT) along with signs and symptoms of clinically relevant bleeding or thrombosis.
Monitor the aPTT but there’s no need to monitor for bleeding or thrombosis signs and symptoms.
Check an INR 4 hours and 8 hours after idarucizumab has been administered.

46. Question 3 - Pharmacist
Patient RK is a 78 year old male weighing 114 kg who presents to the ER after falling at home. The medication history indicates that he was taking warfarin 10 mg PO daily at home, but RK cannot recall his last “Coumadin level.” Upon checking the INR in ER, you find it is supratherapeutic at 8.5. Additionally, after examining the patient, the ER physician is concerned about reversing the effects of the warfarin due to clinical evidence of a subdural hematoma. The physician orders Kcentra and vitamin K 10 mg IV per your health system’s reversal protocol, but looks to you as the pharmacist for Kcentra dosing recommendations. What dose of Kcentra do you recommend for RK?
3500 units
3990 units
5000 units
5700 units

47. Question 4 - Pharmacist
Considering the factor stewardship program implemented at the University of North Carolina Medical Center, which of the following best depicts the potential benefits of a factor product/anticoagulant reversal agent stewardship program?
Optimization of factor product/reversal agent dosing
Evidence-based guideline approaches to care for bleeding patients
Reduced health care expenditures
All of the above

48. Question 1 - technician
Which of the following is best described as a factor product?
Idarucizumab (Praxbind)
Andexanet alfa
aPCC (Feiba NF)
Aripazine

49. Question 2 - technician
Which of the following is best described as a “targeted anti-anticoagulant”, not a factor product?
Kcentra
Andexanet alfa
NovoSeven
Profilnine SD

50. Question 3 - technician
Concerning the administration of idarucizumab, which of the following statements is true?
Appropriate administration may include IV push or IV infusion.
Light protection is a concern for this medication, and the medication can be stored for up to 6 hours at room temperature if exposed to light.
Idarucizumab should be administered over no longer than 5 to 10 minutes if IV infusion selected.
All of the above are true

51. Question 4 - technician
True or False: thromboembolic risk after drug administration is perhaps the most concerning risk associated with Kcentra, and this concern is described in a boxed warning for the medication.