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 warfarininduced 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 warfarinassociated 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: Mortality
Age
Diagnosis
Cause of death
Hospital Day
78 yo male
CNS bleed
herniation/withdr 2
awal of care
41 yo male
GI bleed
GI bleed/arrest
12
76 yo male
GI bleed
GI bleed/arrest
18
88 yo female
CNS bleed
withdrawal of care 8
Results: TAE
Diagnosis
History
TAE
Hospital Day
GI 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
7
15
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.