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

No financial disclosures or conflict of interest

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

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

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.

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

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

Methods - Study Setting•Tertiary care suburban community

teaching hospital•100,000 ED visits per year•700 inpatient beds

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

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

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)

Methods of Measurement•All eligible patients identified by M/W/F

review of FEIBA dispensed to ED

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

Statistical Analysis•Reporting of descriptive measures

(means, medians, IQRs, as appropriate)

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

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

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

Results: MortalityAge Diagnosis Cause of

deathHospital Day

78 yo male CNS bleed herniation/withdrawal of care

2

41 yo male GI bleed GI bleed/arrest 1276 yo male GI bleed GI bleed/arrest 1888 yo female CNS bleed withdrawal of

care8

Results: TAEDiagnosis History TAE Hospital DayGI bleed DVT DVT on US; not

definitively acute vs chronic

3

CNS bleed severe arterial dz, multiple arterial clots, afib, valve

ischemic CVA + arm DVT

715

CNS bleed titanium aortic valve, afib

embolic ischemic CVA

18

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

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

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

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

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

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.

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.