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, MD 1 Catherine Knight, MD 2 Ben-Paul Umunna, MD 2 Mary Hormese, PharmD, BCPS 2 Elise Lovell, MD 2 1 Stanford University, Stanford, CA; 2 Advocate 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 AgeDiagnosisCause of deathHospital Day 78 yo maleCNS bleedherniation/withdr awal of care 2 41 yo maleGI bleedGI bleed/arrest12 76 yo maleGI bleedGI bleed/arrest18 88 yo femaleCNS bleedwithdrawal of care8

19. Results: TAE DiagnosisHistoryTAEHospital Day GI bleedDVTDVT on US; not definitively acute vs chronic 3 CNS bleedsevere arterial dz, multiple arterial clots, afib, valve ischemic CVA + arm DVT 7 15 CNS bleedtitanium aortic valve, afib embolic ischemic CVA 18

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%

23. 23

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.