Download Activated recombinant factor VII after cardiopulmonary bypass

British Journal of Anaesthesia 95 (5): 596–602 (2005)
doi:10.1093/bja/aei244
Advance Access publication September 23, 2005
CARDIOVASCULAR
Activated recombinant factor VII after cardiopulmonary bypass
reduces allogeneic transfusion in complex non-coronary
cardiac surgery: randomized double-blind
placebo-controlled pilot study
P. Diprose1, M. J. Herbertson1y, D. O’Shaughnessy2 and R. S. Gill1*y
1
Department of Anaesthesia and 2Department of Haematology, Southampton University Hospitals,
Tremona Road, Southampton SO16 6YD, UK
*Corresponding author. E-mail: [email protected]
Background. Receiving an allogeneic transfusion may be an independent predictor of mortality
for patients undergoing cardiac surgery. Furthermore, these patients utilize 15% of all donated
blood in the UK. In our unit, 80% of patients undergoing complex non-coronary cardiac surgery
requiring cardiopulmonary bypass (CPB) receive an allogeneic transfusion. Activated recombinant
FVII (rFVIIa) may be effective in reducing this need for transfusion.
Methods. Twenty patients undergoing complex cardiac surgery were randomized to receive
rFVIIa or placebo after CPB and reversal of heparin.
Results. Two patients in the rFVIIa group received 13 units of allogeneic red cells and coagulation
products compared with eight patients receiving 105 units of allogeneic red cells and coagulation
products in the placebo group (relative risk of any transfusion 0.26; confidence interval 0.07–0.9;
P=0.037). The groups did not differ for adverse events.
Conclusion. Despite major limitations (underpowered study and prone to type I error), we have
shown that rFVIIa significantly reduces the need for allogeneic transfusion in complex noncoronary cardiac surgery without causing adverse events.
Br J Anaesth 2005; 95: 596–602
Keywords: blood, coagulation, rFVIIa; blood, transfusion; surgery, cardiovascular
Accepted for publication: July 1, 2005
Cardiac surgery in the UK utilizes 10–15% of all donated
blood, despite evidence that receiving an allogeneic transfusion may have a negative impact on survival after cardiac
surgery.1 2 Furthermore, new variant Creutzfeldt–Jakob
disease (vCJD) is forcing clinicians to re-evaluate their
decision to give patients blood transfusion and may lead
to potential difficulties in maintaining the supply of blood.1 2
Simple, safe and well-documented measures using
licensed therapeutic agents and mechanical devices can
reduce the incidence of an allogeneic transfusion to 15% in
elective first-time coronary artery bypass and valve replacement surgery.3 4 However, allogeneic transfusions may be
administered in up to 80% of patients after complex cardiac
surgery, despite optimal current mechanical and pharmacological therapies. Therefore complex cardiac surgery is an
area where new therapies should be actively pursued in an
attempt to reduce the need for allogeneic transfusion.
Recombinant activated factor VII (rFVIIa) is a novel
haemostatic agent. It is widely used in the management
of patients with haemophilia and inhibitors.5 6 Factor VII
has a pivotal role in coagulation, promoting thrombin
generation locally at the site of blood vessel injury even
when there are other significant deficits in coagulation.7
There is a possible role for rFVIIa in attempting to reduce
life-threatening haemorrhage in patients after cardiac surgery. However, all use of rFVIIa in this setting reported to
date has been open-label uncontrolled use and prone to
publication bias.8–14
y
Declaration of interest. R. S. Gill and M. J. Herbertson undertake
consultancy work for NovoNordisk in the area of clinical trial design
and evaluation. The Department of Haematology, Southampton University Hospitals NHS Trust, has received a research grant from
NovoNordisk. The company has had no role in design, execution
or interpretation of the studies reported.
The Board of Management and Trustees of the British Journal of Anaesthesia 2005. All rights reserved. For Permissions, please e-mail: [email protected]
rFVIIa reduces transfusion after cardiac surgery
Although rFVIIa appears to have been successful, in
open-label reactive use, in reducing allogeneic transfusion
requirements in patients with life-threatening haemorrhage,
we were interested in the potential for rFVIIa to reduce the
need for transfusion in the elective cardiac surgical setting.
Three randomized placebo-controlled studies of prophylactic use of rFVIIa in non-haemophiliac populations have
been reported.15–17 Only one demonstrated efficacy,
where rFVIIa was shown to reduce transfusion requirements
for patients undergoing elective prostatic surgery.17
We hypothesized that the use of rFVIIa after cardiopulmonary bypass (CPB) in complex non-coronary cardiac
surgery would reduce allogeneic transfusion requirements
and would not lead to an excess of adverse thrombotic
events.
Materials and methods
The study was conducted in the cardiothoracic unit of Southampton University Hospitals NHS Trust, Southampton, UK.
After approval from the local research ethics committee and
successful application for an MHRA exemption certificate for
the use of unlicensed medication, patients were approached
for inclusion in the trial. Patients were recruited if they were
aged 18 years or over and scheduled to undergo complex noncoronary cardiac surgery requiring CPB. Inclusion criteria
were repeat non-coronary cardiac surgery, multiple valve
surgeries, aortic root or arch replacements and operations
for endocarditis and aortic dissection. Exclusion criteria
were occurrence of recent thrombotic disease or refusal to
have a transfusion of allogeneic blood or blood products.
Written informed consent was obtained from all patients
who agreed to recruitment into the trial. After consent,
patients were allocated to one of the two treatment groups
using computer-generated random numbers. The rFVIIa
group received rFVIIa 90 mg kg1 after CPB and reversal
of heparin, and the placebo group received an equivalent
volume of saline 0.9% after CPB and reversal of heparin.
The appropriate treatment regime was identified, prepared
and blinded by the pharmacy technical services department.
The drug or placebo solutions were prepared with the only
identifying marks being the patient’s name, study identification number and expiry date. All study investigators,
patients, surgeons, anaesthetists and persons involved in
the patient’s perioperative care were blinded to treatment
allocation. Sealed envelopes were available to facilitate
unblinding should the need arise. Final unblinding of the
study occurred 2 days after the last patient had been
recruited, randomized and treated.
All patients received standard anaesthesia and perioperative care according to the normal practice of the range of
consultant anaesthetists and surgeons involved. This
included the use of aprotinin, a standardized anticoagulation
regimen and a cell-salvage device.
The aprotinin regimen comprised aprotinin 2 million
kallikrein inhibitor units (kiu) intravenously at the start of
surgery, an identical dose into the CPB prime volume and an
intravenous infusion of aprotinin 500 000 kiu h1 throughout the operation.
The anticoagulation regimen comprised heparin
400 IU kg1 to achieve a celite activated clotting time
(ACT) >800 s prior to CPB. If this ACT was not achieved,
further boluses of heparin 100 IU kg1 were administered.
Intraoperative cell salvage (Compact A, Dideco, Sorin
Biomedica, Italy) of shed blood was used from skin incision
until closure of the sternum at the completion of surgery.
On CPB the bypass flow was 2.4 litre min1 m2 and the
trigger for the transfusion of allogeneic red cells was a
haemoglobin concentration <70 g litre1. Mean arterial
pressures were maintained between 50 and 80 mm Hg
using phenylepherine. After rewarming and completion of
the aspects of surgery requiring CPB, patients were weaned
from the CPB machine.
After termination of CPB, heparin was neutralized using
protamine 4 mg kg1. Following this, patients received
either rFVIIa 90 mg kg1 or an equivalent volume of normal
saline. The team caring for the patient were requested not to
transfuse allogeneic blood or coagulation products or to give
any additional intravenous protamine for 10 min after trial
product administration. After aortic decannulation the residual volume within the CPB circuit was drained into the cellsalvage device. Subsequently, this blood and salvaged shed
blood were washed and centrifuged by the cell-salvage
device and then retransfused to the patient.
After admission to the intensive care unit (ICU), the postoperative trigger for transfusion of allogeneic red cells was a
haemoglobin concentration of <85 g litre1. If the patient
bled excessively, coagulation products were administered
according to modification of a protocol previously described
for the management of postoperative cardiac surgical
bleeding (Figure 1).4 The definition of excessive bleeding
was >4 ml kg1 h1 in any one hour, >2 ml kg1 h1 in
any two consecutive hours or >5 ml kg1 in the first 4 h
postoperatively.
Patients’ blood was analysed for standard haematological
variables including haemoglobin concentration, platelet
count, fibrinogen level, international normalized ratio
(INR) and activated partial thromboplastin time (APTR).
Kaolin-activated Thrombelastogram (Haemoscope Corporation, Illinois, USA) data were obtained using standard
and heparinase cups as appropriate. Blood was analysed
preoperatively, on rewarming during CPB, before trial product administration, 10 min after trial product administration
and on admission to the ICU. All results prior to administration of the trial product were available to the intraoperative team caring for the patient in the operating room.
Management of the bleeding patient in the ICU followed
the transfusion protocol (Figure 1). Haemoglobin levels
were recorded on the first postoperative day and just before
hospital discharge.
Primary endpoints were the number of patients receiving
any allogeneic transfusion, the total units of allogeneic red
597
Diprose et al.
Excessive bleeding?
>4 ml kg h–1 in any one hour
>2 ml kg h–1 for two consecutive hours
>5 ml kg–1 in the first four hours post-op
Is urgent re-thoracotomy
necessary?
Yes
For
thoracotomy
and products
according to
consultant
advice
No
If the standard
TEG ‘r’ time is
greater than twice
the heparinase ‘r’
Give 50 mg of
protamine
If platelet count
<100,000x106 litre–1 or
the MA<50 mm
If the heparinase
TEG ‘r’ time
>9 min
Give 1–2 adult bags of
platelets
Give 2– 4 units of
FFP or 1000 iu
prothrombin
concentrate
If the
LY30>7.5%
Give aprotinin 0.5
million unit bolus,
then 0.5 million
units h–1
If the fibrinogen
level <1g litre–1
Give 10 units of
cryoprecipitate
If INR>1.5
with a normal
TEG result
Give 2–4
units of FFP
or 1000 iu
prothrombin
concentrate
Repeat coagulation profile once products infused ⇒ Treat as above if excessive bleeding criteria are met
Fig 1 Product transfusion protocol: TEG, Thrombelastograph data; MA, maximum amplitude; FFP, fresh frozen plasma; LY30, clot lysis at 30 min; r time,
reaction time; INR, International Normalized Ratio.
cells and coagulation products transfused and occurrence of
adverse events.
An audit of the Southampton University Hospitals
cardiothoracic database had shown that 80% of patients
in the control group would be exposed to an allogeneic
transfusion. Sample-size calculations were based on the
power to detect a reduction in the exposure to any allogeneic
transfusion of 40% from a baseline transfusion rate of 80%
with a power of 80% and an a error of 5%. This gave a
sample size of 32 patients per group. We were unable to
secure funding from grant bodies, commercial sources or
NHS Research & Development to purchase 32 (90 mg kg1)
doses of rFVIIa. Thus a decision was made to undertake a
pilot study. Since funds were limited, we recognized that
patients who were unblinded or with major transfusion protocol violations would need to be excluded without further
reallocation being possible.
Data were entered into a database (Microsoft Access
2000); statistical analysis was performed with Analyse-it
for Excel, Leeds, UK (v1.71). Continuous data were analysed for normality with the Shapiro–Wilk W test. Parametric
data were analysed with analysis of variance (ANOVA), and
non-parametric data were analysed with the Kruskal–Wallis
one-way ANOVA by ranks method.18 Fisher’s exact test was
used to calculate relative risks for transfusion between
groups with confidence intervals calculated using Woolf’s
approximation.19
Results
Twenty-four patients scheduled for complex non-coronary
cardiac surgery requiring CPB were approached, and 20
gave informed consent. Patient details and type of operation
are given in Table 1.
One patient from the rFVIIa group was excluded from
the ‘per protocol analysis’ (Table 2). This patient was
unblinded, at surgical request, 2 h after admission to the
ICU when there was sudden onset of serious mediastinal
haemorrhage. This patient incurred multiple transfusion protocol violations and consumed 72 units of allogeneic transfusion and two further doses of rFVIIa. This patient returned
twice to the operating theatre before a posterior aortic tear
was found. This was the only patient who violated the
transfusion protocol or returned to the operating theatre.
The intention-to-treat data are presented in Table 3.
Of the patients who followed the transfusion protocol, two
in the rFVIIa group were exposed to allogeneic transfusion
compared with eight in the placebo group (relative risk of
transfusion 0.26; confidence interval [CI] 0.07–0.9;
P=0.037). In the rFVIIa group 13 units of allogeneic
blood and blood products were transfused compared with
105 in the placebo group. Total units of allogeneic coagulation products were computed from individual units of fresh
frozen plasma (FFP); adult platelet concentrates were
equivalent to 5 units, and each 125 IU of prothrombin complex counted as equivalent to 1 unit of FFP (Table 2).
598
rFVIIa reduces transfusion after cardiac surgery
Table 1 Patient characteristics. Values are given as median (IQR) unless stated otherwise
Age (yr)
Weight (kg)
Euroscore
Cardiopulmonary bypass time (min)
Cross-clamp time (min)
Surgery performed (no. of patients)
Double valve replacement
Redo valve replacement
Aortic root and arch surgery
Combinations of above surgeries
Placebo group (n=10)
rFVIIa group (n=9)
P-value (Kruskal–Wallis
69.5 (63.5–76.5)
65.5 (56.5–76)
6 (4–12)
126 (81.5–178)
97 (51.5–119.5)
63 (59–66)
80.8 (76.8–89.2)
6 (6–8)
114 (76–143)
76 (56–119)
0.19
0.018
0.89
0.97
0.93
5
3
1
1
ANOVA)
2
5
2
0
Table 2 Per protocol patients. Transfusion data are given as median (IQR) units of products or numbers of patients. *Using Fisher exact test
Placebo group (n=10)
Transfusion prior to ICU
Allogeneic red cells
Platelets
Fresh frozen plasma
No. of patients transfused prior to ICU
Transfusion in ICU
Allogeneic red cells
Platelets
Fresh frozen plasma
No. of patients transfused in ICU
Transfusion in whole study
Allogeneic red cells
Platelets
Fresh frozen plasma
Total no. of patients transfused
Total no. of units transfused
Volume of cell-salvaged blood returned to patient (ml)
Total mediastinal drain loss (ml)
rFVIIa group (n=9)
P-value (Kruskal–Wallis
0 (0)
0 (0–1.5)
0 (0–4)
5
0 (0)
0 (0)
0 (0)
1
0.700
0.301
0.139
0.183*
1.5 (0–3.5)
0 (0–1.5)
0 (0–8)
6
0 (0)
0 (0)
0 (0)
1
0.020
0.082
0.039
0.080*
2
1
4
8
105
733
630
(1–3.5)
(0–2)
(0–12.8)
0
0
0
2
13
801
330
(593–878)
(300–965)
(0)
(0)
(0)
(750–934)
(185–765)
ANOVA)
0.030
0.065
0.048
0.037*
0.011
0.22
0.079
Table 3 Intention to treat. Transfusion data given as median (IQR) units of products or numbers of patients. *Using Fisher exact test
Placebo group (n=10)
Transfusion prior to ICU
Allogeneic red cells
Platelets
Fresh frozen plasma
No. of patients transfused prior to ICU
Transfusion in ICU
Allogeneic red cells
Platelets
Fresh frozen plasma
No. of patients transfused in ICU
Transfusion in whole study
Allogeneic red cells
Platelets
Fresh frozen plasma
Total no. of patients transfused
Total no. of units transfused
Volume of cell-salvaged blood returned to patient (ml)
Total mediastinal drain loss (ml)
rFVIIa group (n=10)
P-value (Kruskal–Wallis
0 (0)
0 (0–1.5)
0 (0–4)
5
0 (0)
0 (0)
0 (0)
2
0.627
0.486
0.261
0.35*
1.5 (0–3.5)
0 (0–1.5)
0 (0–8)
6
0 (0)
0 (0)
0 (0)
2
0.095
0.358
0.196
0.17*
2
1
4
8
105
733
630
(1–3.5)
(0–2)
(0–12.75)
0
0
0
3
74
830
330
(593–878)
(300–965)
Haemoglobin concentrations for the two groups are
shown in Table 4. There were no differences between the
groups at any time point. Static tests of coagulation (platelet
count, International Normalized Ratio [INR] and activated
partial thromboplastin ratio [APTR]) for the two groups are
(0–0.75)
(0)
(0–0.75)
(750–926)
(185–855)
ANOVA)
0.111
0.229
0.183
0.07*
0.052
0.198
0.21
shown in Table 5. The INR, which was prolonged in both
groups prior to administration of trial product, returned to
normal at 10 min in the rFVIIa group but was unchanged in
the placebo group. The platelet count was not different
between groups at baseline but was higher in the rFVIIa
599
Diprose et al.
Table 6 Thrombelastograph data. Data are median (IQR). MA, maximum
amplitude
Table 4 Median haemoglobin levels. Data given as median (IQR)
Haemoglobin level (g litre1)
Placebo group
Prior to CPB
131 (119–143.3)
88 (80.8–95.5)
10 min after
study drug
administration
ICU admission
100 (87.3–118.8)
Postoperative day 1 95 (89.5–103)
Prior to hospital
104.5 (98.5–115.5)
discharge
rFVIIa group
P-value
(Kruskal–Wallis
ANOVA)
135 (130–140)
91 (85–102)
0.570
0.414
112 (109–116)
0.391
103 (97–114)
0.270
111.5 (105–122) 0.265
Table 5 Static tests of coagulation. Data given as median (IQR)
Placebo group
Prior to CPB
Platelets (109 litre1) 197 (146–238)
INR
1.15 (1–1.55)
APTR
1.06 (0.89–1.09)
Fibrinogen (g litre1)
3.9 (3.3–4.7)
Before study drug
9
1
Platelets (10 litre ) 113 (74.5–136.8)
INR
2.25 (1.95–2.5)
APTR
1.97 (1.44–2.50)
Fibrinogen (g litre1)
2.3 (2.05–3.15)
10 min after study drug administration
9
1
Platelets (10 litre ) 81 (56–93)
INR
1.95 (1.75–2.25)
APTR
1.54 (1.39–1.79)
1
Fibrinogen (g litre )
2.1 (1.53–2.78)
ICU admission
Platelets (109 litre1) 104 (88–120)
INR
1.6 (1.43–1.96)
APTR
1.79 (1.68–1.91)
1
Fibrinogen (g litre )
2.5 (1.6–3)
rFVIIa group
P-value
(Kruskal–
Wallis
ANOVA)
206 (191–256)
1.2 (1.2–1.3)
1.07 (1.03–1.11)
4.2 (2.4–6.9)
0.488
0.618
0.713
0.757
163 (113–193)
2.3 (2–2.75)
2.04 (1.88–2.49)
2.5 (1.93–2.83)
0.060
0.894
0.689
0.893
119 (91–143)
1 (0.9–1.2)
1.78 (1.54–1.91)
2.4 (2–3.6)
0.016
0.001
0.595
0.270
123 (91–163)
0.9 (0.9–1)
1.85 (1.69–1.95)
2.1 (1.68–3.2)
0.253
0.001
0.653
0.923
Prior to CPB
r time (min)
k time (min)
Angle (deg)
MA (mm)
Before study drug
r time (min)
k time (min)
Angle (deg)
MA (mm)
10 min after study
r time (min)
k time (min)
Angle (deg)
MA (mm)
ICU admission
r time (min)
k time (min)
Angle (deg)
MA (mm)
Placebo group
rFVIIa group
P-value
(Kruskal–Wallis
ANOVA)
5.6
1.6
64.9
65.5
(4.5–7.3)
(1.3–1.8)
(58.2–68.8)
(60.6–67.8)
4.7
1.6
66.5
66.9
(3.3–5.9)
(1.2–1.9)
(58.5–74.2)
(60.5–69.5)
0.413
0.902
0.683
0.903
7.8
2.5
58
51
drug
8.8
2.8
56.4
50.3
(7.5–10.3)
(2.3–4.8)
(42.3–61.1)
(49.8–56)
administration
(5.1–10.8)
(2.2–3.9)
(45–61.7)
(46.7–55.3)
8.5
2.1
63.5
62.3
(7.4–9.2)
(1.7–3.2)
(50.1–66.2)
(56.7–68.6)
0.965
0.25
0.233
0.102
7.4
2.6
53.1
49.1
(6.5–15.3)
(1.8–4.6)
(36.3–61.8)
(46.1–58.1)
1
0.929
0.462
0.87
6.5
2.2
59.3
52.3
(6.2–8.1)
(1.98–2.83)
(53.6–64.8)
(48.8–58.4)
6.5
2.3
59.6
52.5
(5.7–8.5)
(2.2–3.2)
(54.1–61.7)
(47.5–59.4)
0.883
0.462
0.845
1
Table 7 Postoperative events. Data are median (IQR) unless stated otherwise.
MI, myocardial Infarction. *One patient in placebo group who died excluded
from the dataset. yUsing Kruskal–Wallis ANOVA. zUsing Fisher exact test
Placebo group (n=10) rFVIIa group (n=9) P-value
Vent time (h)*
13.5 (6.1–18.5)
ICU stay (days)*
1 (1–4)
Hospital stay (days)*
8 (8–14)
Postoperative stroke
1
Postoperative MI
1
Death
1
group both before and after trial product administration.
After this time there were no significant differences between
the groups’ platelet counts. Thrombelastograph data for the
two groups are shown in Table 6; there were no differences
between the groups at any time.
Length of stay in the ICU, and in the hospital, and occurrence of adverse thrombotic events are shown in Table 7.
There were no differences between the groups for these
times or occurrences.
Discussion
In this pilot study rFVIIa significantly reduced the need for
allogeneic transfusion after complex non-coronary cardiac
surgery. However, the study has a number of limitations.
First, as a result of cost issues, the study is small, underpowered and prone to type I error. The operative groups may
not be equivalent in their relative risk for being transfused.
There is a preponderance of repeat single valves in the
rFVIIa group. However, patients were approached to take
part in the study consecutively, when enough members of
6.1 (4.7–18.5)
2.5 (1–3.5)
11.5 (8.8–19.8)
1
1
0
0.501y
0.434y
0.410y
1z
1z
1z
the research team were present and patients were scheduled
for surgery. The rFVIIa group was heavier than the control
group and small body mass is a recognized risk factor for
needing allogeneic transfusion around the time of cardiac
surgery. Any imbalance in the groups is the result of the
study being small and the nature of random events.
Secondly, again arising from cost restraints, patient
reallocation as a result of unblinding and/or protocol
violation could not be possible. This may have led to an
unrepresentative result. For completeness, both per protocol
and intention-to-treat data are shown in Tables 2 and 3,
respectively.
Thirdly, it could be construed that a lack of protocol for
the transfusion of allogeneic coagulation products, after
CPB and before admission to the ICU, could account for
the differences seen. Before the study started all anaesthetists and surgeons involved were asked to reach a consensus on how to manage patients regarding allogeneic
transfusion during this time period. As this is often a time
of acute haemodynamic instability and blood loss, consensus was not possible. All transfusions during this time period
600
rFVIIa reduces transfusion after cardiac surgery
were reactive as a result of ongoing bleeding after the administration of protamine. The results of Thrombelastograph
and static coagulation tests performed prior to the administration of trial product were available to assist in the management of appropriate transfusion. Patients in the rFVIIa
group received significantly less allogeneic transfusion both
in the ICU where allogeneic transfusion was carefully managed by protocol (Fig. 1), and during the overall operating
theatre and ICU times combined. Therefore we do not
believe that the lack of a protocol to control allogeneic
transfusion during the time in the operating theatre affected
the findings of the study.
Fourthly, patients had a coagulopathy after reversal of
heparin with protamine. It could be construed that the
dose of protamine was inappropriate. However, this dose
is representative of widespread clinical practice.
Fifthly, there was a difference in platelet counts between
the two groups before and after the administration of trial
product. This was on the background of no difference
between the groups’ platelet counts at baseline. Overall
management of patients in the trial, until trial product
administration, was identical. The difference in platelet
counts may be due to the difference in CPB times between
the groups. The impact that this had on allogeneic transfusion is difficult to elucidate, as there is no difference in the
dynamic tests of platelet function (maximum amplitude) on
the Thrombelastograph coagulation analyser.
Finally, it is recognized by the researchers that the prophylactic use of this drug may have resulted in unnecessary
patient exposure to the study drug. However, only two
patients in the placebo group avoided allogeneic transfusion.
This suggests that unnecessary exposure to the trial drug was
very limited.
Bleeding after cardiac surgery is complex in origin. Provided that adequate surgical haemostasis has occurred, the
residual bleeding results from a mixture of hypothermia,
platelet dysfunction and haemodilution of red blood cells
and coagulation factors.20 21 The formation of a stable fibrin
plug at the site of endovascular disruption is a complex
event, with the interaction of circulating VIIa and tissue
factor playing a key initiating role.
The administration of supra-physiological doses of rFVIIa
is safe and efficacious in patients with haemophilia.22 Our
results are in keeping with the only other prophylaxis study
of the use of rFVIIa. This showed, in retropubic prostatectomy, a positive treatment effect in the rFVIIa group.17 It
should be noted that rFVIIa was efficacious at a much smaller dose (40 mg kg1) than in the present study. The dose of
90 mg kg1, in our study, was chosen because patients in the
prostatectomy study did not undergo the coagulopathic
insult of CPB. In addition, the dose of 90 mg kg1 has
been extensively studied, and shown to be safe, in patients
with haemophilia. Our study builds on the results of this
previous work and shows that rFVIIa may be of considerable
use in patients who are at risk of developing coagulopathic
bleeding during complex surgery.
Safety concerns have been raised about the use of this
drug in new settings.23 24 Two recent publications are reassuring. In trauma, a randomized multicentre study has shown
that rFVIIa is safe when given to patients after they had been
resuscitated with at least 8 units of allogeneic blood. In
addition, a well-constructed case cohort study using propensity scoring techniques suggests that the open label use of
rFVIIa for serious haemorrhage after cardiac surgery is not
associated with an increase in adverse events.25 26 However,
there may be concerns about the safety of rFVIIa in patients
without severe bleeding.14 27 At the time of the study design
we were aware of numerous reports of the use of rFVIIa
following coronary artery bypass surgery. However, tissue
factor is expressed at the sites of coronary atheroma.28
Therefore, in the interests of patient safety, we felt that
patients with known coronary vascular disease should be
excluded.
The financial cost of rFVIIa is a further issue. Our transfusion service provided us with the unit costs for allogeneic
blood products used in the study. Allogeneic product costs
for the placebo group were £10 000, compared with £2000
for the rFVIIa group. However, the rFVIIa used cost
£32 000. This must be weighed against the possible benefits
to the patients involved. In those patients where adequate
surgical haemostasis was achieved, the use of rFVIIa prevented the transfusion of 92 units of allogeneic blood and
blood products, and reduced the risk of receiving any allogeneic transfusion by 74%.
In this pilot study, we have shown that rFVIIa may have
exciting potential in cardiac surgery. However, its true
efficacy and safety profile will not be known until further
appropriately powered randomized trials are performed.
Acknowledgements
We would like to thank Ms K. Golder for invaluable help with data collection. An unrestricted educational grant from NovoNordisk to Dr Denise
O’Shaughnessy was used to purchase rFVIIa for this study.
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