David Barounis , MD 1 Catherine Knight, MD 2 Ben-Paul Umunna , MD 2

1. Factor Eight Inhibitor Bypassing Activity (FEIBA) for the Rapid Reversal of Major Bleeding in Patients with Warfarin Induced Coagulopathy: A Pilot Study David Barounis, MD1 Catherine Knight, MD2 Ben-Paul Umunna, MD2 Mary Hormese, PharmD, BCPS2 Elise Lovell, MD2 1Stanford University, Stanford, CA; 2Advocate Christ Medical Center, Oak Lawn, IL

2. No financial disclosures or conflict of interest

3. Background • Fresh frozen plasma (FFP) + vitamin K to reverse major bleeding due to warfarin associated coagulopathy • FFP shortcomings • incomplete reversal • time delay for ABO compatibility, thawing • large volume • time to transfuse • risk of TRALI • Prothrombin complex concentrates (PCC) recommended since 2012

4. FEIBA • Plasma derived • 4 coagulation factors (II, VII, IX, X) • FDA approved in hemophilia • Small volume • No blood typing/thawing

5. Clinical Experience with FEIBA • Retrospective comparison of 72 pts receiving FEIBA to 69 patients receiving FFP • Median time to reversal of INR < 1.4 was 2 hours in FEIBA group, 25 hours in FFP group • 7% TAE, 22% mortality in FEIBA group Wojcik C, Schymik ML, Cure EG. Activated prothrombin complex concentrate factor VIII inhibitor bypassing activity (FEIBA) for the reversal of warfarin-induced coagulopathy. Int J Emerg Med 2009;2:217-225.

6. Study Purpose • To evaluate the efficacy and safety of FEIBA and IV vitamin K for the reversal of warfarin-associated coagulopathy in patients with major hemorrhage

7. Hypothesis • The use of FEIBA and IV vitamin K will result in the rapid reversal of warfarin associated coagulopathy in patients with major bleeding • Adverse event rate will be low

8. Methods - Study Setting • Tertiary care suburban community teaching hospital • 100,000 ED visits per year • 700 inpatient beds

9. Methods - Study Design • Ongoing prospective, observational study • ED patients on warfarin presenting with major bleeding • INR ≥ 5.0 1000U of FEIBA • INR < 5.0  500U of FEIBA IV • 10mg IV vitamin K • Repeat INR 30 minutes, 4 and 24 hours

10. Inclusion Criteria • Age > 18 • Present to the ED with major hemorrhage while on warfarin • life or limb threatening bleed or • bleed in critical location (intracranial, ophthalmic, intraspinal) or • 2 gram fall in hemoglobin • Initial INR >1.5

11. Exclusion Criteria • Coagulopathy not due to warfarin • On warfarin, but INR ≤ 1.5 • No major hemorrhage • Received additional reversal agents prior to/in ED (FFP, aFactor VII, PCCs, vitamin K PO/SQ/IM)

12. Methods of Measurement • All eligible patients identified by M/W/F review of FEIBA dispensed to ED

13. Outcome Measures • Primary Outcome: Time to INR ≤ 1.5 • Secondary outcomes: • Thrombotic adverse events, allergic reaction • FEIBA dose required to reverse • Units of PRBCs transfused • Mortality

14. Statistical Analysis • Reporting of descriptive measures (means, medians, IQRs, as appropriate)

15. Results • Between 2/8/2013 and 8/30/2013, 44 ED patients received FEIBA • 9 did not meet inclusion criteria • 6 not major bleed • 3 INR ≤ 1.5 • 14 patients excluded • 6 FFP or alternate route vitamin K • 4 died before consent obtained • 1 no POA • 1 withdrew consent • 2 ethical issue to approach for consent

16. Results • 21 patients enrolled • 11 CNS bleed, 8 GI bleed, 1 Hematuria, 1 Pulmonary hemorrhage • Mean initial INR was 5.5 • 16/21 patients admitted to ICU for at least 1 day • Achieved INR ≤ 1.5 in all patients • Mean time to INR ≤ 1.5 was 127 minutes • 1 patient’s repeat INR was drawn ~12 hrs after FEIBA • if this patient excluded, mean time to INR ≤ 1.5 was 98 minutes

17. Results • Four (19%) patients died (none with TAE) • 2 GI bleed • 2 CNS bleed • Four thrombotic adverse events (TAE) in 3 (14%) patients • 2 ischemic CVAs • 2 extremity DVTs

18. Results: Mortality

19. Results: TAE

20. TAE: Background • Kcentra: 9% TAE vs. 5.5% TAE in FFP group (ns) • Wojcik: 1.4% TAE in FFP group • MEDENOX trial: 15% rate of DVT in patients admitted without SQ enoxaparin • FEIBA in hemophilia: TAE rate of 4 per 100,000 infusions

21. Limitations • Single center • Observational study design • Disease oriented primary outcome • 4 patients died before consent obtained (impacts mortality rate) • Contribution of FEIBA to thrombotic adverse events uncertain

22. Conclusions • FEIBA and IV vitamin K result in rapid reversal of warfarin-induced coagulopathy in patients with major bleeding • Thrombotic adverse event rate was 14%

24. What about Kcentra? • FDA approved April 30, 2013 • PCC given along with Vitamin K • Factors II, VII, IX, X, with proteins C and S, antithrombin III • Includes heparin • Dosing based on INR, body weight • No repeat dosing • Known risks

25. Cost of FEIBA vs FFP • Feiba: $1.48 per unit • Hospital cost: $740 for 500 units, $1480 for 1000 units • Patient cost: $3,496 and $5,920 • FFP: $65 -70 per unit, start with 10 cc/kg, 200 cc in unit of FFP, so 100 kg pt needs 5 units FFP = $350

26. 4 Patients with 3 TAEs • Leg DVT, 2 ischemic CVAs, and arm DVT.  One pt with both arm DVT and CVA.   • Pt with leg DVT admitted with GI Bleed, had h/o DVT. US hospital day 3 with DVT which could not be definitively called acute versus chronic. • Pt with arm DVT and CVA admitted with acute on chronic subdural hematoma, h/o severe arterial disease/multiple peripheral arterial clots, also mitral valve replacement, afib • Pt with other CVA (thought to be embolic) admitted with SAH, had h/o titanium aortic valve and afib.

27. Clinical Experience with FEIBA • FEIBA usage summarized in 16 patients at community hospital • 87% of patients survived to discharge • No signs or symptoms of TAE Stewart WS, Pettit H. Experiences with an activated 4-factor prothrombin complex concentrate (FEIBA) for reversal of warfarin-related bleeding. AJEM 2013; 31:1251-1254.