Transcript Factor VII in Cardiac Surgery

rFactor VIIa in Cardiac Surgery
Timothy H. Trotter, MD, FACS
Assistant Professor of Surgery
IRB Approval
OUHSC IRB Protocol #12376
VAMC IRB Protocol #12376
Assistance
Mary Lane, PhD -- Data analysis
Shannie Frisbie -- Cost information
The residents and fellows for providing
me with the opportunity to use rFVIIa
FDA Approved Uses for
rFactor VIIa
“…management of bleeding related to
hemophilia in patients with factor
inhibitors…”
A number of “off label” uses have
become popular since it was first used
for treatment of traumatic bleeding after
a GSW in 1999
Davidson, et al. Blood
Coagulation & Fibrinolysis
2003; 14:175-79.
Clotting Factor Changes in CPB
 Decrease in Factors may be important in CPB
 Harker -- decrease in Factors not important
 Based on observations of single deficiency pts
 The following changes have been observed :
 Factor II
 Factor V
51% Decrease
28% Decrease
 Falls before CPB
 Less fall with adequate heparinization
 Factor VII
27% Decrease
 Ca. 28% fall in the PCV due to dilution
 Factor X
 Factor VIII
56% Decrease
No Change
rFactor VIIa Mechanism of Action
 406 amino acid Vitamin K-dependent
glycoprotein
 Generation of thrombin by initial binding to
tissue factor and activation of FX on the
platelet surface
 It also participates in conversion FIX-->FIXa
 Activation of FX in combination with FV
converts prothrombin to thrombin leading to
the formation of a hemostatic “plug” &
subsequently converts fibrinogen to fibrin
causing local hemostasis
rFactor VIIa Mechanism of Action
Partial activation of thrombin occurs at
rFVIIa concentrations of 50nM, but full
activation of thrombin or “thrombin burst”
occurs at 100-150nM
This thrombin activity on the platelet
leads to a stabilized thrombin plug and
tight fibrin structure resistant to lysis
rFactor VIIa Mechanism of Action
The “thrombin burst” and stabilized
“plug” seems to only occur at sites
where tissue factor is exposed at sites of
vessel injury
This is probably why there is little
generalized thrombosis with rFVIIa
rFactor VIIa Mechanism of Action
 The decrease in fibrinolysis is thought to
possibly be due to an increase in thrombinactivatable fibrinolysis inhibitor and an
increase in FXIIIa
 rFVIIa appears to work in a TF-independent
fashion directly on FIX/FX on the phospholipid
surface of the activated platelet
Eikelboom, et al. Blood Coagulation
& Fibrinolysis 2003, 14:713-17.
Hemostatic Mechanisms for rFVIIa
rFactor VIIa Half Life
The mean elimination half life of rFVIIa is
3.8-5.8 hours (only 1.3 hours in children)
Prothrombin time is shortened by rFVIIa
treatment
rFactor VIIa Dosing
Dosage
Micrograms/Kg
Time to
Treatment
Excellent or
Effective
Response %
Mean Number
of Doses
Compassionate
Use
60-120
5 days
72
13.6
Dose Finding
70
9 hours
72
3.6
35
9 hours
53
3.5
90
1.2 hours
92
2.3
US Home
Treatment
rFactor VIIa Dosing
 Most authors will admit that there is little real
science for the dosing of rFVIIa and most
authorities recommend that the dosing be
based on weight, but that the dose be rounded
to the nearest vial
 Continuous infusions do not seem to provide
any benefit and the dosing scheme is no more
clear than bolus
Novo Nordisk data, rFVIIa,
20 March 2001.
Adverse Effects of rFVIIa
 As of March 2001, an estimated 171,790
doses had been sold with 87 reported adverse
events:
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16 Decreased therapuetic response
7 MI’s (all pt’s had predisposing factors)
4 PE’s
6 Ischemic CVA’s
3 Venous Thromboses
1 DIC
17 died and 8 were felt to be related to the rFVIIa
 1:21,474 related to rFVIIa
Levi, et al. Crit Care Med
2005; 33:883-90.
Adverse Effects of rFVIIa
 Levi et al reviewed 483 papers related to the
pharmacologic use of rFVIIa
 Used for hemophilia with inhibiting antibodies,
Glanzmann Thrombasthenia, congenital FVII
deficiency, liver disease, cirrhosis, surgery/trauma,
reversal of anticoagulant therapy, and excessive
blood loss
 They found that in patients other than hemophilia
patients the estimated incidence of
thromboembolism is 1.4%
Raobaikady, et al. BJA
94(5):586-91.
Surgical Uses of rFVIIa
 Raobaikady et al looked at the use of rFVIIa in
a double-blind, randomized, placebocontrolled study in 48 patients undergoing
surgery for major traumatic fracture of the
pelvis or the pelvis/acetabulum and found no
decrease in the volume of blood loss in
patients with normal hemostasis
Karkouti, et al. Transfusion
2005; 45:26-34.
Cardiac Surgery and rFVIIa
Karkouti et al looked at 51 patients with
intractable blood loss after cardiac
surgery using a propensity scorematched case-control analysis
 They used about 70micrograms/kg in
severe bleeding and 35micrograms/kg in
“less severe, controlled bleeding”
Karkouti, et al. Transfusion 2005;
45:26-34.
Characteristics of Karkouti Pts
VARIABLE
rFVIIa PATIENTS %
GENERAL POP %
p VALUE
Mean Age
56
62
0.0007
Urgent Surgery
27
8
<0.0001
Redo Surgery
35
8
<0.0001
CHF
48
21
<0.0001
Active Endocarditis
8
1
<0.0001
Complex Surgery
73
24
<0.0001
Mean CPB Period (min)
159
100
<0.0001
DHCA
15
3
<0.0001
Difficult Wean from CPB
46
13
<0.0001
LCOS
25
4
<0.0001
Reexploration
60
6
<0.0001
Massive Blood Loss
92
8
<0.0001
Units Blood, Cryoppt
10
0
<0.0001
PRBC
14
1
<0.0001
Platelets
15
0
<0.0001
FFP
10
0
<0.0001
Karkouti, et al. Transfusion
2005; 45:26-34.
Matched Control Pts
The matched control patients were
essentially no different from the rFVIIa
patients except in the volume of blood
products that they received
Karkouti, et al. Transfusion 2005;
45:26-34.
Postoperative Course Karkouti Pts
ADVERSE EVENT
GENERAL POP
rFVIIa PATIENTS
MATCHED CONT PT
Duration Intub (hrs)
14
62
64
ICU LOS (days)
1
6
3.5 (p <0.05)
Hosp LOS (days)
7
15.5
10 (p <0.05)
CVA
1.4
4
1
MI
2.2
3
4
PE/DVT
0.2
1
0
Liver Dysfunction
N/A
2
3
Renal Dysfunction
N/A
15
6 (p <0.05)
Death
0.4
7
7
Composite
N/A
21
15
Recovery Measures
Adverse Event
Karkouti, et al. Transfusion
2005; 45:26-34.
Karkouti Conclusions
 The hourly blood loss profile after the
administration of rFVIIa is similar to that seen
in the control and is significant
 1/3 of the patients required a second dose and
all of those patients had a surgically
correctable cause
 rFVIIa was found to reduce intractable blood
loss, but with an increase in morbidity
 ICU LOS, Hosp LOS, Renal Dysfunction, ? CVA
Ravio et al, Ann Thorac
Surg 2005; 80:66-71.
Cardiac Surgery and rFVIIa
 Raivio et al reported the use of rFVIIa in 16
postop cardiac surgery patients
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10 patients were “emergency”
6 patients required DHCA
4 were redo patients
All were complex cardiac or aortic procedures
Mean predicted EuroSCORE mortality was 19.8%
Hospital mortality was 25%
Mean ICU stay was 21 days
Mean dose was 65 micrograms/kg
Ravio et al, Ann Thorac
Surg 2005; 80:66-71.
Raivio Bleeding Pre/Post rFVIIa
6 Hours Before
rFVIIa
6 Hours After
rFVIIa
p Value
2180
350
<0.001
Platelets
12
0
0.005
FFP
3.0
1.0
0.017
PRBC
4.0
2.0
NS
Bleeding (ml)
Transfusions
(Units)
Ravio et al, Ann Thorac
Surg 2005; 80:66-71.
Raivio Conclusions
 82% of the patients had an obvious
hemostatic response
 25% had “severe postoperative
thromboembolic or thrombotic complications”
 All of the Heart or Heart/Lung transplant
patients died
 They recommend caution in the use of rFVIIa
Cost Concerns
 The cost of rFVIIa is significant
 1.2 mg, 2.4mg, and 4.8 mg vials
 2.4 mg “costs” $850 at VAMC
 2.4 mg “costs” $2184 at OUMC
 Estimated cost in literature is about $5000 for a 90
mcg/kg dose in a 70kg patient
 Cost to OUMC 8/04-8/05 for 46 doses in 35
patients was $299,240
 However, the cost of intractable bleeding is
also high
 Average incremental increase in cost of $3,866
 Bleeding requiring reexploration increases
mortality 7-fold (15.4%) and the additional cost is
$10,000
Oklahoma City VAMC and rFVIIa
rFVIIa was first used at the OKC VAMC
for intractable post-Cardiotomy bleeding
in December 2002
Since that time 16/564 patients have
received rFVIIa
Demographics
 16 patients Mean Age
63.9 yrs (54-76)
 Elective
37.5%
 Urgent
43.75%
 Emergency
18.75%
 Amicar
18.75%
 Aprotinin
75%
 Nothing
6.25%
 Few of these patients were receiving IIb/IIIa
inhibitors/Plavix
Patient Characteristics
 Mean Preop EF
 Mean rFVII Dose
 Mean NYHA/CCS
 Mean CPB Time
49%
87.83 mcg/kg
3.19/2.94
211 min
 One OPCAB Patient
 Mean Operative Time
 Mean Intubation Time
 Mean SICU Days
 Mean Hospitalization Days
413 min
53 hours
7.0 days
11.45 days
Patie n t Diagn osis
O peration
1
AI, Ao
Aneurysm
2
3
ASCAD
Acute MI,
IABP in
Cath Lab
ASCAD
ASCAD
MS
Valved
Conduit,
CABGx1
BHCABx4
BHCABx6
4
5
6
7
8
9
10
11
12
13
14
15
16
BHCABx4
BHCABx5
Open Mitral
Valvotomy
AI,
AVR,
Endocarditis Toronto,
CABGx3
ASCAD
BHCABx3
MR,
BHCABx4,
ASCAD
MV Repair,
MVR
75% LM,
BHCABx3,
NSCCA
Wedge LLL
AI, MR,
AVR Root
Endocarditis Synergraft ,
MVR
Mosiac
95% LM,
BHCABx2
IABP in
Cath Lab
MR,
MVR,
ASCAD
CABGx3,
T V Repair
Stanford A, Elephant
PFO
T runk, PFO
ASCAD
OP CABx4
Metastatic
Repair of Ao
NSCCA
Arch
Emerge n cy Re do PO
An tifi brin olytic Mil ri n
Re op
Elective
No
No
Aprotinin
Yes
Urgent
Emergency
No
No
Yes
No
Aprotinin
Aprotinin
Yes
Yes
Elective
Elective
Elective
No
Yes
No
No
No
No
Aprotinin
Aprotinin
Aprotinin
No
Yes
Yes
Urgent
No
No
Aprotinin
Yes
Elective
Elective
No
Yes
No
No
Amicar
Aprotinin
No
Yes
Urgent
No
No
Amicar
No
Urgent
No
No
Aprotinin
Yes
Emergency
No
No
Aprotinin
Yes
Elective
Yes
No
Aprotinin
Yes
Elective
No
No
Aprotinin
No
Elective
Emergency
No
No
Yes
No
Nothing
Amicar
No
No
Pati e nt O perati on Hemostasi s
After
rFVIIa
1
Valved
Yes
Conduit,
CABG
2
BHCABx4 Yes
Dose
IC U
of
Days
rFVIIa
9000
6
CPB De ath
Ti me
Mi n
215 No
12711
8
180
No
3
4
5
6
7
8
9
10
11
12
13
14
15
16
C au se
of
De ath
O th er
Myoglob
C ompli cati on
None
4854
Reop for
?Left
hemothorax
None
None
None
1058
BHCABx6
BHCABx4
BHCABx5
Open
Mitral
Valvot omy
AVR,
Toront o,
CABGx3
BHCABx3
Yes
Yes
Yes
Yes
8190
7740
7200
7240
11
4
3
NA
260
123
286
192
No
No
No
Yes, in
OR
Yes
9000
4
248
No
None
4926
Yes
6300
4
78
None
2208
BHCABx4,
MV
Repair,
MVR
BHCABx3,
Wedge
LLL
AVR Root
Synergraft ,
MVR
Mosiac
BHCABx2
MVR,
CABGx3,
T V Repair
Elephant
T runk,
PFO
OP CABx4
Yes
6030
205
422
Yes,
P ulm
1month Bleed
PO
Yes
MSOF,
DNR
ARF, Sepsis,
CVVHD
3986
Yes
7560
6
162
Yes
None
3369
Yes
7200
6
266
No
ND
Yes
Yes
12550
12000
3
53
67
323
No
Yes
Creat rose t o
4.0 then
declined, No
HD required
None
Yes
6930
13
190
No
No
9000
5
0
No
Repair of
Ao Arch
Yes
7200
17
97
Yes
Lung
Bleeding
MSOF
MSOF,
DNR
9464
3725
2497
ND
ND
ND
ND
Tie off of
SVG
Cerebral
Mets,
DNR
ND
ND
Total Blood Product Use
45
40
35
30
25
20
15
10
5
0
Pre-FVII
Post-FVII
Total Blood Use
p<0.001
Blood Usage in Pts With rFVIIa
Postop
60
50
40
Pre-FVII
Post-FVII
30
20
10
0
Pt 4
Pt 6
Pt 7
Pt 8
Pt 14
Pt 15
Cell Saver Use Pre/Post-FVII
25
20
15
Pre-FVII
Post-FVII
10
5
0
1 2 3 4 5 6 7 8 10 11 12 13 14 15 16
PRBC Use Pre/Post-FVII
20
18
16
14
12
10
8
6
4
2
0
Pre-FVII
Post-FVII
1 2 3 4 5 6 7 8 10 11 12 13 14 15 16
Platelet Use Pre/Post-FVII
4
3.5
3
2.5
Pre-FVII
Post-FVII
2
1.5
1
0.5
0
1 2 3 4 5 6 7 8 10 11 12 13 14 15 16
FFP Use Pre/Post-FVII
5
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
Pre-FVII
Post-FVII
1 2 3 4 5 6 7 8 10 11 12 13 14 15 16
Cryoppt Use Pre/Post-FVII
40
35
30
25
Pre-FVII
Post-FVII
20
15
10
5
0
1 2 3 4 5 6 7 8 10 11 12 13 14 15 16
Chest Tube Output/Hr
450
400
350
300
250
200
150
100
50
0
-1
PreFVII
CT Output
2
4
6
8
10
12
Outcomes
 2/16 patients were returned to the OR for reexploration
 One was bleeding from a side branch of a SVG
 One had stopped bleeding and had only about
250-500ml of blood total in the left chest and
mediastinum
 This represents all of the patients returned (with or
without rFVIIa) for the past 4 years
Mortality
 6/16 patients died
 1/16 (6.25%) died in the OR/within 30 days
 5/16 died from 36 to 208 days later
 31.25% overall mortality for these patients
 Overall mortality 4.1% (23/564) from 12/02-7/05
 5/16 of these deaths were attributed as Operative
Mortality by CICSP and these are included in the 4.1%
Time To Death
250
208
200
150
Days to Death
100
50
0
83
67
43
36
Pt 4
Pt 7
0
Pt 9
Pt 10
Pt 15
Pt 16
Future Directions
rFVIIa, while expensive, may be less
expensive than re-exploration
rFVIIa may salvage some patients who
otherwise would not have survived
Is there a role for rFVIIa earlier in the
care of these patients?
Other Issues
 Other Off-label uses for rFVIIa
 Relative contraindications to transfusion
 Multiple RBC allo-antibodies
 Refractoriness to platelet transfusions
 ?? Plavix poisoning
 IgA deficiency who should not get FFP
 Jehovah’s Witnesses
 When is the best time to give rFVIIa?
 Who decides who gets and when to give
rFVIIa?