Netherlands Journal

netherlands journal of critical care
in one hour of an initial CT scan, both of which occurred within 4
hours of symptom onset [31]. The end points of the study were the
change in volume of the haematoma as assessed by repeat CT scans
and clinical outcome. Patients receiving rFVIIa had significantly less
increase in the haematoma volume. The placebo group had a 29%
increase in the haematoma at 24 hours compared to an increase of
16%, 14% and 11% for the 40, 80 and 160mcg/kg groups respectively.
Overall, pooled data for all doses resulted in a 52% relative reduction
in haematoma volume compared with placebo. Patients receiving
rFVIIa had significantly less disability at three months compared to
patients receiving placebo, and there was a 38% relative reduction in
mortality. Finally, there was a trend to suggest that earlier administration
and larger doses produced improved end points.
However, there was an increase in thromboembolic events including
seven patients with myocardial infarction and nine with cerebral
infarction in the treatment groups. Overall there were two serious
thromboembolic events in the placebo group and 21 in the treatment
group. This difference was significant although the number of fatal
or disabling thromboembolic events was not significantly increased.
On the basis of this study, rFVIIa will probably become a useful therapeutic
agent although the ideal dose and patient population at high
risk of ischaemic complications is yet to be identified.
Thromboembolic Complications
A recent article has reviewed the number of thromboembolic complications
(TECs) that have been voluntarily reported to the American
federal Drug Administration following rFVIIa use over a five year period
[82]. During this time, there were 168 reports that were deemed
to be true TECs secondary to rFVIIa, 28 of which were in patients with
haemophilia. This compares with 4 520 patients who received rFVIIa
in the year 2004 alone. Of the 168 TEC’s, there were 39 cerebro-vascular
events, 34 acute myocardial infarctions, 32 pulmonary emboli
and 42 deep vein thromboses.
There were also splenic, retinal vein, femoral and renal artery thromboses.
Eighteen percent occurred within two hours of the last dose
of rFVIIa (compatible with the elimination half-life of 2.3 hours for
rFVIIa) and 52% of TECs occurred within 24 hours. There were 36
deaths that were thought to be due to the TEC. However only 102
cases of the 168 included a causality assessment of which 81 were
deemed to be probably or possibly secondary to the rFVIIa. Finally
there were also 193 reports pertaining to a lack of benefit following
administration.
Conclusion
There is a significant body of evidence to suggest that rFVIIa is safe
with only minimal thrombo-embolic complications. There are also
many ‘last-ditch’ case reports illustrating a beneficial effect of rFVIIa
in a number of life-threatening surgical and non-surgical clinical settings.
And if this drug is present within the hospital, it becomes emotionally
and ethically difficult not to use it as a rescue therapy in lifethreatening
haemorrhage. However, there is undoubtedly a degree
of positive bias reporting in the literature when describing rFVIIa in
this clinical scenario. Also, in an era of increasing concern regarding
the rapidly expanding public health expenditure, rFVIIa remains
a very costly therapy whose non-evidenced based, off-licence use may
impact on the provision of other therapies.
In those areas where clinical efficacy has been relatively established
such as in patients with haemophilia or patients with a recent
intracerebral haemorrhage, we would recommend the use of rFVIIa
as described by the trials. In the majority of clinical settings though,
there is a lack of prospective randomised-controlled trials of rFVIIa.
Thus far, the few that have been performed have shown minimal
mortality benefit. Without a body of well performed, randomisedcontrolled
trials, we would recommend that the use of this agent is
reserved for last ditch salvage situations where all conventional treatments
have at least been initiated, and shown to have failed in patients
with life-threatening surgical bleeding.
References
1. Hedner U, Kisiel W. Use of human factor VIIa in the
treatment of two haemophilia A patients with high titer
inhibitors. J Clin Invest 1983;71:1836-1841
2. Abshire T, Kenet G. Recombinant factor VIIa : review of
efficacy, dosing regimens and safety in patients with
congenital and acquired factor VIII or IX inhibitors. J
Thromb Haemost 2004;2:899-909
3. Kenet G, Walden R, Eldad A, Martinowitz U. Treatment of
traumatic bleeding with recombinant factor VIIa. Lancet
1999;354:1879
4. O’Neill PA, Bluth M, Gloster ES, Wali D, Privolos S, DiMaio
TM et al. Successful use of recombinant activated factor
VII for trauma associated hemorrhage in a patient without
pre-existing coagulopathy. J Trauma 2002;52:400-
405
5. Rapaport SI, Rao LV. The tissue factor pathway : how
it has become a ‘prima ballerina’. Thromb Haemost
1995;74:7-17
6. Hoffman M, Monroe DM III. A cell-based model of haemostasis.
Thromb Haemost 2001;85:958-965
7. Drake TA, Morrissey JH, Edgington TS. Selective cellular
expression of tissue factor in human tissues. Implications
for disorders of haemostasis and thrombosis. Am J
Pathol 1989;134:1087-1097
8. Wilcox JN, Smith KM, Schwartz SM, Gordon D. Localization
of tissue factor in the normal vessel wall and in
the atherosclerotic plaque. Proc Natl Acad Sci USA
1989;86:2839-2843.
9. Lawson JH, Kalaftis M, Stram S, Mann KG. A model for
the tissue factor pathway to thrombin. I. An empirical
study. J Biol Chem 1994;269:23357-23366
10. Hoffman M, Monroe DM III. The action of high-dose
factor VIIa (FVIIa) in a cell-based model of haemostasis.
Semin Hematol 2001;38:6-9
11. Pusateri AE, Park MS. Mechanistic implications for the
use and monitoring of recombinant activated factor VII
in trauma. Crit Care 2005;9(Suppl 5):S15-S24
12. Lisman T, De Groot PG. Mechanism of action of recombinant
factor VIIa. J Thromb Haemost 2003;1:1138-1139
13. Van’t Veer C, Mann KG. The regulation of the factor VIIdependent
coagulation pathway : rationale for the effectiveness
of recombinant factor Viia in refractory bleeding
disorders. Semin Thromb Hemost 2000;26:367-372
14. Monroe DM, Hoffman M, Oliver JA, Roberts HR. Platelet
activity of high-dose factor VIIa is independent of tissue
factor. Br J Haematol 1997;99:542-547
15. Lisman T, Adelmeijer J, Cauwenberghs S, Van Pampus
EC, Heemskerk JW, De Groot PG. Recombinant factor
VIIa enhances platelet adhesion and activation under
flow conditions at normal and reduced platelet count. J
Thromb Haemost 2005;3:742-751
16. He S, Blomback M, Jacobsson EG, Hedner U. The role of
recombinant factor VIIa (FVIIa) in fibrin structure in the
absence of FVIII/FIX. J Thromb Haemost 2003;1:1215-1219
17. Lisman T, Mosnier LO, Lambert T, Mauser-Bunschoten EP,
Meijers JC, Nieuwenhuis HK et al. Inhibition of fibrinolysis
by recombinant factor VIIa in plasma from patients
with severe haemophilia A. Blood 2002;99:175-179
18. Telgt DS, Macik BG, McCord DM, Monroe DM, Roberts HR.
Mechanism by which recombinant factor VIIa shortens
the aPTT: activation of factor X in the absence of tissue
factor. Thrombosis Research 1989;56:603-9
19. Hendricks HG, Meijer K, Dewdt JT, Porte RJ, Klompmaker
IJ, Lip H et al. Effects of recombinant activated factor
VII on coagulation measured by thromboelastography
in liver transplantation. Coagulation and Fibrinolysis
2002;13:309-13
20. Hoffman M. Laboratory monitoring of high dose factor
VIIa therapy. Annals of Internal Medicine 2003;139:791
21. Spahn DR, Rossaint R. Coagulopathy and blood component
transfusion in trauma. British Journal of Anaesthesia
2005;95:130-9
22. Grounds RM, Bolan C. Clinical experiences and current
evidence for therapeutic recombinant factor VIIa treatment
in nontrauma settings. Critical Care 2005;9(Suppl
5):S29-36
23. Martinowitz U, Michaelson M. Guidelines for the use of
recombinant activated factor VII (rFVIIa) in uncontrolled
bleeding : a report by the Israeli Multidisciplinary rFVIIa
Task Force. J Thromb Haemost 2005;3:640-648
24. www.hemophilia.org/News/medicalnews/mn_06_09_
05.htm
25. Bernstein DE, Jeffers L, Erhardtsen E et al. Recombinant
Factor VIIa corrects prothrombin time in cirrhotic
patients: a preliminary study. Gastroenterology
1997;113:1930-7
26. Roberts HR, Monroe DM, White GC. The use of recombinant
factor VIIa in the treatment of bleeding disorders.
Blood 2004;104: 3858-3864T18
27. Lindley CM, Sawyer TW, Macik BG, Lusher J, Harrison JF,
Baird-Cox K et al. Pharmacokinetics and pharmacodynamics
of recombinant factor VIIa. Clinical Pharmacology
and Therapy 1994;55:638-48
546
neth j crit care • volume 10 • no 5 • october 2006