1. Update on Reversal Agents
for TSOACs
American Venous Forum
28th
Annual Scientific Meeting
Orlando, FL 2016

2. Disclosures
Marlin W. Schul, MD, RVT, FACPh
Indiana Vascular Associates, LLC
3920 St. Francis Way, Ste 105
Lafayette, IN 47905
mschul@lafayetteveins.com
I have nothing to disclose

3. FDA Indications

4. Benefits of TSOACs
• Easy Compliance, e.g. 1-2/day
• Predictable pharmacokinetics
• Short half-lives
• Few drug interactions
– P-glycoprotein inhibitors/inducers
– CYP3A4 inhibitors/inducers
1 (800) Bad Drug, e.g. Wide
Spread use is limited without
clear antidote when major life
threatening bleeding occurs.

5. Bleeding Challenges
• Unlike warfarin with clear reversal process
• Vit K, Coag Factor Replacement with prothrombin
complex concentrate (PCC)

6. New Drug Testing Challenges
• Patient variability
– Sensitivity & Specificity of routine tests, e.g.
PT/Bleeding times, etc.;
– Thromboelastography is not widely available;
– Safety of drugs, e.g. low rate of bleeding;
– Difficult translation animals to humans;
– Coagulation tests are surrogates and may
NOT reflect efficacy in bleeding control.

7. Nonspecific Reversal
• PCC
• Activated PCC
• Recombinant Factor VIIa (rVIIa)
• Aripazine/Ciraparantag

8. Prothrombin Concentrate
Complex
• Developed for Vitamin K antagonist rapid
reversal for bleeding or need for urgent surgery.
– Ingredients: II, VII, IX, X, Protein C&S, & Heparin
– Dec. PT yet no effect on APPT or anti-Xa activity
• VTE Incidence 1.4%
Zahir H, Brown KS, Vandell A; 2015; Circulation. 131(1):82-90.
At highest dose 50U/kg, significant reduction of bleeding occurred after single
60 mg edoxaban dose. Lesser dose of PCC had no meaningful effect.

9. Activated PCC “Factor VIII
Inhibitor”
• Designed for hemophiliacs w/hemorrhage
– Ingredients: II, VII, IX, & X
– Corrected abnormal thrombin generation indices
• VTE Incidence (4-8 events /10 infusions)
Recombinant factor VIIa
• Designed for hemophiliacs w/hemorrhage
– Ingredients: II, VII, IX, & X
– Corrected abnormal thrombin generation indices
• VTE Incidence (4-8 events /10 infusions)

10. Aripazine (PER977)
• Small synthetic water soluble molecule that
binds directly: UFH, LMWH, Iia & Xa inhibitors
preventing OACs from binding to endogenous
targets.
– Single IV dose dec. bleeding rat tail to all drugs;
– Single IV dose dec. bleeding in liver laceration model;
– N180 healthy volunteers: 100-300 mg reversed 60
mg edoxaban dose & sustained effect for 24h
Potential Universal Antidote

11. Specific Reversal Agents
• Idarucizumab
– Dabigatran specific
• Andexanet alfa
– Factor Xa Derivative
• Xa inhibitors
• LMWH

12. Idarucizumab
• Humanized mouse fragment monoclonal Ab
specific to Dabigatran
– Dose dependent dec. blood loss in tail transection
– Bleeding Pig Model (Blunt Liver Injury) dec. blood loss
& inc. survival
– Dec. anticoag. effects in volunteers with CRI
– Phase III underway
• Prelim indications ability to reverse bleeding within minutes
as 33/36 operative hemostasis was considered normal
FDA Approval 16-OCT-15
Fast track approval path.

13. Andexanet alfa
Andexanet Alfa, a recomb.
human Factor Xa molecule from
hamster ovaries.
•33 healthy subjects (55-73 Yr)
•Anticoag activity reversed by
94% within 2-5 minutes (p <
0.0001)
•Effect lasts ~ 1-2 hours
•Restoration of thrombin
generation to pre-anticoagulant
levels
•No subjects developed Ab to
Factor X or Xa

14. When & How to Reverse
Active Bleeding
• Minor/Moderate
– Withdraw OAT
– Consider mechanical/surgical
(endovascular approach)
• Severe/Life Threatening
– Admin nonspecific reversal
agent(s)
• PCC 50 U/kg
• APCC 80 U/kg
– Admin idarucizumab in
dabigatran subjects
Overdose
• CRI, Overdose, Drug
Interactions
– Unclear if high levels increase
bleeding risk, e.g. dose
escalation trial showed no inc.
bioavailability in doses above
40mg rivaroxaban or 25 mg
apixaban
Siegal DM. J Thromb Thrombolysis 2015; 39:
395-402
Kubitza D, Becka M, Roth A, et al. Curr Med
Res Opin 2008; 24(10): 2757-2765.

15. Consensus Recommendations
Kaatz S, Kouides PA, Garcia, DA, Spryopoulos AC, Crowther M, et al. “Guidance on the
emergent reversal of oral thrombin and factor Xa inhibitors.” Am J Hematol 87: S141-
S145.
Dabigatran – Praxibind (idarucizumab)
Xa Inhibitors – Andexanet alfa pending fast track approval
HMWH, LMWH, Xa, DTI – PER977 (aripazine)