rFactor VIIa in Cardiac Surgery

Timothy H. Trotter, MD, FACS

Assistant Professor of Surgery

IRB Approval

OUHSC IRB Protocol #12376VAMC IRB Protocol #12376

Assistance

Mary Lane, PhD -- Data analysisShannie Frisbie -- Cost information

The residents and fellows for providing me with the opportunity to use rFVIIa

FDA Approved Uses forrFactor 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

Clotting Factor Changes in CPBDecrease 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 51% Decrease Factor V 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 56% Decrease Factor VIII No Change

Davidson, et al. Blood Coagulation & Fibrinolysis 2003;

14:175-79.

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 thrombin-activatable 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

Hemostatic Mechanisms for rFVIIa

Eikelboom, et al. Blood Coagulation & Fibrinolysis

2003, 14:713-17.

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

US Home Treatment

90 1.2 hours 92 2.3

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

Adverse Effects of rFVIIa

As of March 2001, an estimated 171,790 doses had been sold with 87 reported adverse events: 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

Novo Nordisk data, rFVIIa, 20 March

2001.

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%

Levi, et al. Crit Care Med 2005; 33:883-90.

Surgical Uses of rFVIIa

Raobaikady et al looked at the use of rFVIIa in a double-blind, randomized, placebo-controlled 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

Raobaikady, et al. BJA 94(5):586-91.

Cardiac Surgery and rFVIIa

Karkouti et al looked at 51 patients with intractable blood loss after cardiac surgery using a propensity score-matched case-control analysisThey 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

Recovery Measures

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)

Adverse Event

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

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

Karkouti, et al. Transfusion 2005; 45:26-

34.

Cardiac Surgery and rFVIIa

Raivio et al reported the use of rFVIIa in 16 postop cardiac surgery patients 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

Bleeding (ml) 2180 350 <0.001

Transfusions (Units)

Platelets 12 0 0.005

FFP 3.0 1.0 0.017

PRBC 4.0 2.0 NS

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

Ravio et al, Ann Thorac Surg 2005;

80:66-71.

Cost ConcernsThe cost of rFVIIa is significant1.2 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 49%Mean rFVII Dose 87.83 mcg/kgMean NYHA/CCS 3.19/2.94Mean CPB Time 211 min

One OPCAB Patient

Mean Operative Time 413 minMean Intubation Time 53 hoursMean SICU Days 7.0 daysMean Hospitalization Days 11.45 days

Patient Diagnosis Operation Emergency Redo PO Reop

Antifibrinolytic Milrin

1 AI, Ao Aneurysm

Valved Conduit, CABGx1

Elective No No Aprotinin Yes

2 ASCAD BHCABx4 Urgent No Yes Aprotinin Yes 3 Acute MI,

IABP in Cath Lab

BHCABx6 Emergency No No Aprotinin Yes

4 ASCAD BHCABx4 Elective No No Aprotinin No 5 ASCAD BHCABx5 Elective Yes No Aprotinin Yes 6 MS Open Mitral

Valvotomy Elective No No Aprotinin Yes

7 AI, Endocarditis

AVR, Toronto, CABGx3

Urgent No No Aprotinin Yes

8 ASCAD BHCABx3 Elective No No Amicar No 9 MR,

ASCAD BHCABx4, MV Repair, MVR

Elective Yes No Aprotinin Yes

10 75% LM, NSCCA

BHCABx3, Wedge LLL

Urgent No No Amicar No

11 AI, MR, Endocarditis

AVR Root Synergraft, MVR Mosiac

Urgent No No Aprotinin Yes

12 95% LM, IABP in Cath Lab

BHCABx2 Emergency No No Aprotinin Yes

13 MR, ASCAD

MVR, CABGx3, TV Repair

Elective Yes No Aprotinin Yes

14 Stanford A, PFO

Elephant Trunk, PFO

Elective No No Aprotinin No

15 ASCAD OPCABx4 Elective No Yes Nothing No 16 Metastatic

NSCCA Repair of Ao Arch

Emergency No No Amicar No

Patient Operation Hemostasis After rFVIIa

Dose of rFVIIa

ICU Days

CPB Time Min

Death Cause of Death

Other Complication

Myoglob

1 Valved Conduit, CABG

Yes 9000 6 215 No None 4854

2 BHCABx4 Yes 12711 8 180 No Reop for ?Left hemothorax

1058

3 BHCABx6 Yes 8190 11 260 No None 9464 4 BHCABx4 Yes 7740 4 123 No None 3725 5 BHCABx5 Yes 7200 3 286 No None 2497 6 Open

Mitral Valvotomy

Yes 7240 NA 192 Yes, in OR

Lung Bleeding

ND

7 AVR, Toronto, CABGx3

Yes 9000 4 248 No None 4926

8 BHCABx3 Yes 6300 4 78 Yes, 1month PO

Pulm Bleed

None 2208

9 BHCABx4, MV Repair, MVR

Yes 6030 205 422 Yes MSOF, DNR

ARF, Sepsis, CVVHD

3986

10 BHCABx3, Wedge LLL

Yes 7560 6 162 Yes MSOF None 3369

11 AVR Root Synergraft, MVR Mosiac

Yes 7200 6 266 No Creat rose to 4.0 then declined, No HD required

ND

12 BHCABx2 Yes 12550 3 67 No None ND 13 MVR,

CABGx3, TV Repair

Yes 12000 53 323 Yes MSOF, DNR

ND

14 Elephant Trunk, PFO

Yes 6930 13 190 No ND

15 OPCABx4 No 9000 5 0 No Tie off of SVG

ND

16 Repair of Ao Arch

Yes 7200 17 97 Yes Cerebral Mets, DNR

ND

Total Blood Product Use

05

1015202530354045

Total Blood Use

Pre-FVIIPost-FVII

p<0.001

Blood Usage in Pts With rFVIIa Postop

0

10

20

30

40

50

60

Pt 4 Pt 6 Pt 7 Pt 8 Pt 14 Pt 15

Pre-FVIIPost-FVII

Cell Saver Use Pre/Post-FVII

0

5

10

15

20

25

1 2 3 4 5 6 7 8 10 11 12 13 14 15 16

Pre-FVIIPost-FVII

PRBC Use Pre/Post-FVII

02468

101214161820

1 2 3 4 5 6 7 8 10 11 12 13 14 15 16

Pre-FVIIPost-FVII

Platelet Use Pre/Post-FVII

0

0.5

1

1.5

2

2.5

3

3.5

4

1 2 3 4 5 6 7 8 10 11 12 13 14 15 16

Pre-FVIIPost-FVII

FFP Use Pre/Post-FVII

00.5

11.5

22.5

33.5

44.5

5

1 2 3 4 5 6 7 8 10 11 12 13 14 15 16

Pre-FVIIPost-FVII

Cryoppt Use Pre/Post-FVII

0

5

10

15

20

25

30

35

40

1 2 3 4 5 6 7 8 10 11 12 13 14 15 16

Pre-FVIIPost-FVII

Chest Tube Output/Hr

050

100150200250300350400450

-1Pre-FVII

2 4 6 8 10 12

CT Output

Outcomes

2/16 patients were returned to the OR for re-exploration 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

36

83

0

208

6743

0

50

100

150

200

250

Pt 4 Pt 7 Pt 9 Pt 10 Pt 15 Pt 16

Days to Death

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?