Update on Reversal Agents for TSOACsAmerican Venous Forum

28th Annual Scientific MeetingOrlando, FL 2016

DisclosuresMarlin W. Schul, MD, RVT, FACPhIndiana Vascular Associates, LLC3920 St. Francis Way, Ste 105Lafayette, IN 47905mschul@lafayetteveins.com

I have nothing to disclose

FDA Indications

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.

Bleeding Challenges

• Unlike warfarin with clear reversal process• Vit K, Coag Factor Replacement with prothrombin

complex concentrate (PCC)

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.

Nonspecific Reversal

• PCC• Activated PCC• Recombinant Factor VIIa (rVIIa)• Aripazine/Ciraparantag

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.

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)

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

Specific Reversal Agents

• Idarucizumab – Dabigatran specific

• Andexanet alfa – Factor Xa Derivative

• Xa inhibitors• LMWH

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.

Andexanet alfaAndexanet 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

When & How to ReverseActive 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.

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)