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REVIEW ARTICLE
Endorsed by
9
The role of recombinant activated
factor VII in cardiac surgery
A. Richardson, M. Herbertson, R. Gill
Shackleton Department of Anaesthesia, Southampton University Hospitals NHS Trust
ABSTRACT
Recombinant factor VIIa may reduce surgical blood loss and transfusion of blood products in cardiac surgery.
However, the true risks of its use in this setting remains to be elucidated, especially when it is administered
with other potent pro-haemostatic agents. We reviewed the recent literature on this topic and suggest that the
off label use of recombinant factor VIIa is likely to continue. It is our institutional practice to use it in the op-
erating room at a dose of 90mcg/Kg to ensure there is no obvious correctable surgical source of blood loss, and
to be certain that bleeding has stopped before the chest is closed.
Keywords: recombinant factor VII, cardiac surgery, bleeding, transfusion.
InTRoduCTIon mofiltration, prolonged ventilation and in-
tensive care unit stay (7). Novel haemostat-
Bleeding is a common complication follow- ic agents may have role in reducing surgical
ing cardiac surgery, leading to transfusion blood loss and the associated transfusion of
and/or surgical re-exploration. Both inter- blood products.
ventions are associated with significant
cost, in terms of both risk to the patient
and financial outlay to the healthcare sys- REComBInAnT FACToR VIIA
tem (1).
Perioperative allogeneic red cell and hae- Recombinant factor VIIa (rFVIIa) is li-
mostatic component transfusion has been censed for the prevention and treatment of
shown to be associated with increased bleeding in patients with haemophilia with
length of intensive care unit and hospital auto-antibodies to coagulation factors VIII
stay (2), increased infection rates (3), in- or IX, FVII deficiency, and acquired haemo-
creased rates of every postoperative morbid philia. The binding of VIIa to perivascular
event (4), and decreased short- and long- tissue factor (TF) initiates coagulation, al-
term survival rates (5, 6). though the process can only progress be-
Re-exploration is associated with signifi- yond the generation of small amounts of
cant increases in mortality, the need for thrombin when the injury allows platelets
intra-aortic balloon counter-pulsation, hae- and larger proteins to leave the vascular
space and adhere to TF-bearing cells in the
Corresponding author: perivascular area. However, TF may also be
Ravi Gill, BM, FRCA
expressed on activated neutrophils, mono-
Shackleton Department of Anaesthesia
Southampton University Hospitals NHS Trust cytes and microparticles.
Tremona Road, Southampton SO16 6YD, UK
The exact role of this circulating TF remains
e.mail: [email protected]
A. Richardson, et al.
10 controversial, as under normal conditions suggested doses in the order of 40-100 mcg/
it is thought to be inactive or encrypted (8). kg in the setting of uncontrolled post-cardi-
Thus, although the effects of VIIa are be- ac surgical haemorrhage, with second doses
lieved to be localized predominantly to the considered if no response is seen after 30 to
site of vessel injury, concerns remain about 60 minutes (10).
the potential for thrombotic complications
arising from its use. The complex nature of
haemostasis and the role rFVIIa plays have EFFICACy
been previously described (9).
The consensus is that rFVIIa reduces bleed-
ing after cardiac surgery, as evidenced by a
uSE reduction in chest tube drainage and red
cell and component therapy transfusion
The medical literature increasingly de- rates. Some authors have found that these
scribes “off-label” rFVIIa use to treat severe effects are more sustained with increasing
bleeding after major surgery in patients rFVIIa doses. There is also evidence that
without haemophilia. Whilst some studies rates of surgical re-exploration for bleeding
have used it to prevent bleeding and trans- are reduced (11, 12). However the majority
fusion (prophylaxis), the majority have of trials have been underpowered, whilst
used it as rescue therapy when convention- case reports and series are subject to posi-
al surgical exploration and blood product tive reporting and publication bias.
and anti-fibrinolytic agent administration
has failed to arrest bleeding.
It has therefore rarely been studied in iso- AdVERSE EVEnTS
lation from other pro-haemostatic agents.
The majority of trials have reported on Since cardiopulmonary bypass may up-
rFVIIa use in adults; some have examined regulate the expression of systemic tis-
the paediatric population. The range of sur- sue factor, the main focus of concern has
gical procedures in which it has been used been inappropriate thrombosis associated
has been comprehensive, with a significant with rFVIIa use in the cardiac surgical
rate of redo cardiac surgery in the adult set- setting. Interestingly, the incidence of ad-
ting (10). verse thrombotic events is almost zero in
the paediatric population. This may have
something to do with their naive vascular
doSE endothelium. Observational uncontrolled
data from the US Food and Drug Admin-
The optimal dosing regime for rFVIIa in istration adverse event reporting system
the post-cardiac surgical setting remains reveals an alarming 1 in 50 thromboem-
unclear. The reported dose range for single bolic complication rate (associated with a
bolus administration has been broad (11.1 0.5% mortality) when “off label” rFVIIa
– 180 mcg/kg), although many have used is used in a diverse range of patients (13).
single doses of 90 mcg/kg or less. Some In cardiac surgery, mortality and compli-
studies have limited treatment to a single cation rates of patients who have failed to
bolus dose, whilst others have used repeat- respond to standard transfusion therapy
ed doses at varying intervals. Recommen- and then received rFVIIa are within range
dations made by various expert panels have of 19% to 40%. The lack of control pa-
The role of recombinant activated factor VII in cardiac surgery
tients in most of these case series makes in this context. Thus, it remains to be seen 11
it difficult to determine whether the re- whether rFVIIa use may reduce the mid- to
ported adverse events are related to the late-term complications of red cell transfu-
administration of rFVIIa or the critical sion, such as pulmonary dysfunction and
unstable condition of patients when they sepsis. There is currently no consensus on
received rFVIIa (14-17). When rFVIIa has the appropriate “off-label” dose of rFVIIa.
been used on a compassionate basis to re- Since the thrombin-generation response to
duce uncontrolled bleeding in 51 patients VIIa depends on the availability of other
after cardiac surgery, propensity match- coagulation factors and platelets, it would
ing techniques to adjust for baseline risks seem that the ‘optimal’ rFVIIa dose will
demonstrated that the rates of serious vary according to the degree of transfusion
adverse events were equivalent (18). In a of other blood products. This will need to
group of patients with very high risk of be accounted for when planning future
stroke, a matched analysis of patients re- studies. Given the uncontested efficacy of
ceiving rFVIIa after major ascending and rFVIIa in preventing and reducing bleed-
aortic arch reconstructive surgery sug- ing and transfusion, it’s “off label” use is
gested stroke rates were equal (19). A re- likely to continue.
cent multicentre randomized clinical trial Clinicians must be aware of both the poten-
of rFVIIa in patients actively bleeding af- tial risk and benefits when using this po-
ter cardiac surgery showed a non-signif- tent thrombin-generating agent. It is our in-
icant trend to an increase in the rates of stitutional practice to use it in the operating
thromboembolic complications. This trial room at a dose of 90mcg/Kg to ensure there
demonstrated a 50 % reduction in reoper- is no obvious correctable surgical source of
ation rates for bleeding and as expected a blood loss, and to be certain that bleeding
marked dose-dependant decrease in trans- has stopped before the chest is closed.
fusion rates in those patients randomized
to rFVIIa (11). Dr Herbertson and Dr Gill worked on adviso-
ry boards for Novo Nordisk; Dr Gill received
speaker fees from Novo Nordisk.
dISCuSSIon
REFEREnCES
There appears to be general agreement that
1. Freedman J, Luke K, Monga N, et al. A pro-
rFVIIa has the potential to reduce bleeding,
vincial program of blood conservation: The
blood product administration and re-oper-
Ontario Transfusion Coordinators (ONTraC).
ation rates post-cardiac surgery. However,
Transfus Apher Sci 2005; 33: 343-349.
these are not outcomes in themselves, and 2. Hein OV, Birnbaum J, Wernecke KD, et al.
the true risks of its use in this setting re- Three-year survival after four major post-car-
main to be elucidated, especially when it is diac operative complications. Crit Care Med.
administered with other potent pro-haemo- 2006; 34: 2729–2737.
static agents. The under-powering of trials 3. Murphy PJ, Connery C, Hicks GL Jr, Blumberg
N. Homologous blood transfusion as a risk fac-
performed to date mean that differentiation
tor for postoperative infection after coronary
between adverse events arising specifically
artery bypass graft operations. J Thorac Car-
from rFVIIa use, and arising generally from
diovasc Surg 1992; 104: 1092-1099.
the critical condition of those receiving is
4. Koch CG, Li L, Duncan A, et al. Morbidity and
currently impossible. There has also been mortality risk associated with red blood cell
a lack of longer-term follow-up in studies and blood-component transfusion in isolated
A. Richardson, et al.
12 coronary artery bypass grafting. Crit Care Med surgery: a meta-analysis. J Cardiothorac Vasc
2006; 34: 1608-1616. Anesth 2009; 23: 34-40.
5. Koch CG, Li L, Duncan AI, et al. Transfusion 13. O’Connell KA, Wood JJ, Wise RP, et al. Throm-
in coronary artery bypass grafting is associated boembolic adverse events after use of recom-
with reduced long-term survival. Ann Thorac binant human coagulation factor VIIa. JAMA
Surg 2006; 81: 1650-1657. 2006; 295: 293-298.
6. Surgenor SD, Kramer RS, Olmstead EM, et al. 14. McCall P, Story DA, Karapillai D. Audit of fac-
The association of perioperative red blood cell tor VIIa for bleeding resistant to conventional
transfusions and decreased long-term survival therapy following complex cardiac surgery.
after cardiac surgery. Anesth Analg 2009; 108: Can J Anaesth 2006; 53: 926-933.
1741-1746. 15. von Heymann C, Redlich U, Jain U, et al. Re-
7. Choong CK, Gerrard C, Goldsmith KA, et al. combinant activated factor VII for refractory
Delayed re-exploration for bleeding after coro- bleeding after cardiac surgery: a retrospective
nary artery bypass surgery results in adverse analysis of safety and efficacy. Crit Care Med
outcomes. Eur J Cardiothorac Surg 2007; 31: 2005; 33: 2241-2246.
834-838. 16. Herbertson M. Recombinant activated factor
8. Smith SA. The cell-based model of coagulation. VII in cardiac surgery. Blood Coagul Fibrinoly-
J Vet Emerg Crit Care 2009; 19: 3-10. sis 2004; 15: S31-S32.
9. Monroe DM, Hoffman M. What does it take 17. Isbister J, Phillips L, Dunkley S, et al. Recom-
to make the perfect clot? Arterioscler Thromb binant activated factor VII in critical bleeding:
Vasc Biol. 2006; 26: 41-48. experience from the Australian and New Zea-
10. Warren O, Mandal K, Hadjianastassiou V, et land Haemostasis Register. Intern Med J. 2008;
al. Recombinant activated factor VII in cardiac 38: 156-165.
surgery: a systematic review. Ann Thorac Surg 18. Karkouti K, Yau TM, Riazi S, et al. Determi-
2007; 83: 707-714. nants of complications with recombinant fac-
11. Gill R, Herbertson M, Vuylsteke A, et al. Safe- tor VIIa for refractory blood loss in cardiac
ty and efficacy of recombinant activated factor surgery. Can J Anaesth 2006; 53: 802-809.
VII. A randomized placebo-controlled trial in 19. Tritapepe L, De Santis V, Vitale D, et al. Re-
the setting of bleeding after cardiac surgery. combinant activated factor VII for refractory
Circulation 2009; 120: 21-27. bleeding after acute aortic dissection surgery: a
12. Zangrillo A, Mizzi A, Biondi-Zoccai G, et al. propensity score analysis. Crit Care Med 2007;
Recombinant activated factor VII in cardiac 35: 1685-1690.
