Use of activated recombinant coagulation factor VII in patients undergoing reconstruction surgery for traumatic fracture of pelvis or pelvis and acetabulum: a double-blind, randomized, placebo-controlled trial{dagger},{ddagger}

R. Raobaikady1, J. Redman, J. A. S. Ball2, G. Maloney3 and R. M. Grounds*

Department of Anaesthesia and Intensive Care, St George's Hospital, London, UK Present addresses: 1 Department of Anaesthesia and Intensive Care, York Hospital, York, UK. 2 Intensive Care Unit, Liverpool Hospital, NSW, Australia. 3 Department of Anaesthesia, Mayo General Hospital, Co. Mayo, Ireland

* Corresponding author: Department of Anaesthesia and Intensive Care Medicine, St George's Hospital, Blackshaw Road, London SW17 0QT, UK. E-mail: michael.grounds{at}stgeorges.nhs.uk

Accepted for publication January 21, 2005.


    Abstract
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 Footnotes
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. Activated recombinant coagulation factor VII (rFVIIa) effectively prevents and controls bleeding in patients with coagulopathy. Data show that rFVIIa may reduce blood loss and eliminate the need for transfusion in patients with normal haemostasis undergoing major surgery. We assessed the efficacy of rFVIIa in patients with normal haemostasis undergoing repair surgery of major traumatic fracture of the pelvis or the pelvis and acetabulum, who were expected to have a large volume of blood loss.

Methods. We performed a double-blind, randomized, placebo-controlled trial involving 48 patients undergoing major pelvic–acetabular surgery. Patients were randomized to receive an i.v. bolus injection of rFVIIa 90 µg kg–1 or placebo as add-on therapy at the time of the first skin incision. All patients also received intraoperative salvaged red blood cells (RBC).

Results. There was no significant difference in the total volume of perioperative blood loss, the primary outcome variable, between the rFVIIa and placebo groups. In addition, there were no differences between the two groups in the total volume of blood components, including salvaged RBC transfused, number of patients requiring allogeneic blood components, total volume of fluids infused, total operating time, time taken after entry to the intensive care unit to reach normal body temperature and acid–base status, and time spent in hospital. No adverse events, in particular thromboembolic events, were reported in either group.

Conclusions. In patients with normal haemostasis undergoing repair surgery of traumatic pelvic–acetabular fracture, the prophylactic use of rFVIIa does not decrease the volume of perioperative blood loss.

Keywords: blood, coagulation, recombinant FVIIa ; blood, loss ; surgery, repair of traumatic, pelvic–acetabular fracture


    Introduction
 Top
 Footnotes
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Reconstruction surgery of major pelvic–acetabular fractures can be associated with large volumes of blood loss. Despite the use of intraoperative red blood cell (RBC) salvage, transfusions of allogeneic RBC and other blood components are still needed in most patients undergoing these complex surgical procedures.1 Blood transfusion is associated with a number of infectious and non-infectious complications.24 Hence, several blood conservation approaches and haemostatic agents have been investigated with the aim of reducing blood loss and the need for allogeneic blood components.

Activated recombinant coagulation factor VII (rFVIIa) is currently approved for the management of bleeding in patients with congenital haemophilia with inhibitors, acquired haemophilia, congenital factor VII deficiency, and Glanzmann's thrombasthenia with refractoriness to platelet transfusion. In addition, anecdotal data show that rFVIIa is haemostatically effective in several other settings, mainly in the presence of impaired haemostasis.59

Our study investigated the efficacy of rFVIIa in reducing perioperative blood loss in patients with normal haemostasis undergoing orthopaedic surgery for repair of major traumatic pelvic–acetabular fracture.


    Patients and methods
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 Footnotes
 Abstract
 Introduction
 Patients and methods
 Results
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The study was a randomized, double-blind, placebo-controlled trial conducted at St George's Hospital between August 2002 and March 2004. The trial protocol was approved by the local Institutional Ethics Committee and written informed patient consent was obtained.

Patients (18–60 yr old) with major pelvic–acetabular fracture caused by trauma who were scheduled for semi-elective ‘large’ reconstruction surgery with the potential of blood loss exceeding 50% of circulating blood volume were included in the trial. The definitions of ‘large’ reconstruction surgery10 are shown in Table 1.


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Table 1 Definitions of large reconstruction pelvic trauma surgery

 
Exclusion criteria were a history of thrombosis (deep vein thrombosis, pulmonary embolism, cerebral thrombosis), severe head injuries or an abnormal CT scan of the head due to head injuries, base deficit of greater than 15 mEq litre–1 or severe acidosis (pH<7.0.) before surgery, body weight exceeding 135 kg, known or suspected allergy to any drug that may be administered during the course of the study, cardiac arrest after trauma and before surgery at St George's Hospital, known congenital bleeding disorders, known pregnancy or positive pregnancy test at enrolment, previous participation in this study, previous receipt of rFVIIa within 48 h of screening, and currently participating or having participated in another investigational drug study within the last 30 days.

After screening, patients who met the inclusion criteria were randomized to the rFVIIa or placebo group, with a computer-generated 1 to 1 randomization scheme. Recombinant FVIIa (NovoSeven®; Novo Nordisk, Bagsvaerd, Denmark) 90 µg kg–1 or placebo was given i.v. as a bolus at the first skin incision. A second injection of the same dose was given 2 h after the first dose if the transfusion of allogeneic RBC was indicated by an intraoperative measurement of haemoglobin concentration of <8.0 g dl–1 after the retransfusion of salvaged RBC.

The surgery was performed according to the local standard practice at St George's Hospital. Moreover, throughout the study period, the following transfusion guidelines were adhered to: allogeneic RBC were transfused when haemoglobin was <8.0 g dl–1; platelets when platelet count <100x109 litre–1; fresh frozen plasma (FFP) when prothrombin time-international normalized ratio (PT-INR) or activated partial thromboplastin time (APTT) was >1.5 times normal; and cryoprecipitate when fibrinogen concentration was <0.8 g litre–1. In addition, intraoperative salvaged RBC were retransfused to every patient. During surgery, haemoglobin was measured hourly using Haemocue.12 13

Prophylactic anticoagulant with low molecular weight heparin (dalteparin) 2500 U s.c. was given once a day during the preoperative period up to 12 h before surgery and the same dose was restarted 12 h after surgery or once it was decided that no further surgical intervention was required and clotting results were normal. This was continued until warfarin was commenced and therapeutic INR levels were achieved. After surgery the warfarin was given for a minimum of 6 weeks and stopped only when full mobilization was achieved. In patients with acetabular fractures only, and to reduce the incidence of periacetabular heterotrophic ossification, indomethacin was commenced before surgery and continued for the duration of hospitalization. All surgical procedures were carried out under general anaesthetic only.

The primary outcome variable was the total volume of perioperative blood loss. The perioperative period was defined as the intraoperative period combined with the 48 h after the first dose of rFVIIa or placebo. The total volume of blood loss was measured using a technique described previously14 and was the sum of blood loss measured by use of suction apparatus, the red cell salvage apparatus, weighing swabs and drapes and postoperative wound drains less the fluid used for irrigation by the surgical team. Moreover, in a post hoc analysis, the total blood loss was also calculated using a method recently described by Rosencher and colleagues for the Orthopaedic Surgery Transfusion Hemoglobin European Overview Study (OSTHEO).15 Secondary outcome variables were perioperative transfusion requirement (total volume of allogeneic blood components and salvaged RBC, total number of units of allogeneic blood components), number of patients transfused with allogeneic blood components, total volume of crystalloid (Hartmann's solution, dextrose saline, normal saline) and colloid (succinylated gelatin) fluids infused, total operating time, time taken after entry to intensive care unit (ICU) or recovery unit to reach normal body temperature (36.3–37.1°C) and acid–base status (blood pH 7.35–7.45 with standard base excess –2 to +2), time spent in ICU after surgery, days of hospitalization, and number of times a patient was returned to the operating theatre. In addition, coagulation parameters (PT, APTT) were measured immediately before and 2 h after the administration of rFVIIa or placebo, then on admission to ICU and 24 h later. Adverse events, focusing on thromboembolic adverse events, were monitored for 7 days and then on day 30 after surgery. Thromboembolic adverse events were monitored clinically and by Doppler ultrasound. Venograms would only be performed when there were clinical indications.

The calculation of sample size was based on our historical data on perioperative blood loss (mean 2818 ml, SD 1442 ml), and the assumption that blood loss would be decreased by approximately 45% in patients treated with rFVIIa. Forty-eight patients were included in the trial to achieve 80% power at a 5% significance level.

Results from the rFVIIa and placebo groups were compared using the unpaired t-test, the unpaired t-test after logarithmic transformation of data, the Wilcoxon rank sum test, and Fisher's exact test as appropriate. The significance level was set at 0.05.


    Results
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 Footnotes
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
All 48 patients who met the inclusion criteria completed the study and were included in the analysis (Fig. 1). Patient characteristics were comparable between the rFVIIa and placebo groups (Table 2). Furthermore, the types of surgery were well matched, 12 patients in each group undergoing acetabular reconstruction and receiving indomethacin. Nine patients (38%) in each arm of the study received a second dose of rFVIIa or placebo.



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Fig 1 Flow diagram of patient disposition.

 

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Table 2 Patient characteristics.

 
The results are summarized in Table 3. The median total volumes of measured perioperative blood loss were 2070 ml in the rFVIIa group and 1534 ml in the placebo group. The difference did not differ significantly (P=0.79). The difference in the volume of intraoperative blood loss was also not statistically significant (P=0.57). Measured median postoperative blood loss was significantly lower in the rFVIIa group (240 ml) compared with the placebo group (370 ml, P=0.022). The calculated perioperative blood loss using the Rosencher et al.15 method produced slightly different results from the measured blood loss; nevertheless, the difference between the median perioperative blood loss in the rFVIIa (2146 ml) and placebo (2787 ml) groups was not significant (P=0.50).


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Table 3 Trial results. Median (range) when applicable.

 
The total volumes of perioperative transfusion requirement, including salvaged RBC, were 289 ml in the rFVIIa group and 706 ml in the placebo (P=0.33). Eleven (46%) patients in the rFVIIa group received allogeneic blood components compared with 16 (67%) patients in the placebo. This difference was not statistically significant (P=0.24). All patients who were transfused with allogeneic blood components received only RBC, except one patient in the rFVIIa group who also received FFP and one in the placebo who also received platelets, FFP and cryoprecipitate. The median number of units of allogeneic RBC transfused was 0 in the rFVIIa and 2 in the placebo groups. The difference was not statistically significant (P=0.34).

The mean total operating time in both groups was approximately 3 h. After surgery, patients in both groups spent similar time in the ICU or recovery unit. Furthermore, the time taken after entry to ICU to reach normal body temperature and acid–base status was not different between the two groups (data not shown), and neither was the time spent in hospital.

Two patients were returned to the operating theatre. One patient in the placebo group had developed severe postoperative retroperitoneal bleeding and was returned to the theatre 36 h after surgery. Although the volume of postoperative bleeding in the drain was only 80 ml, the retroperitoneal blood loss was estimated to be 5 litres. The volume of blood loss used for the calculation in this patient was 80 ml. The bleeding was found to have a surgical cause. One patient in the rFVIIa group was returned to the operating theatre because the surgeons were not satisfied with the acetabular fixation.

In both the rFVIIa and placebo groups, the PT-INR at the start of surgery was within the normal range. In the rFVIIa group, the value was shortened from 0.94 at the start of surgery and before rFVIIa administration to 0.67 2 h later. The PT-INR returned to the baseline value when measured 24 h after admission to the ICU. In the placebo group, the mean PT-INR remained unchanged. The APTT ratios in the rFVIIa group and the placebo group were within the normal range throughout the trial period. Overall, there was no significant difference in haemoglobin levels, platelet counts, fibrinogen concentrations, PT-INR and APTT ratios between the two groups. (Tables 4 and 5).


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Table 4 Haemoglobin concentration. Mean (range).

 

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Table 5 Platelet count (PLT), fibrinogen (Fg) concentration, prothrombin time (PT) and activated partial thromboplastin time (APTT) during the perioperative course. Mean (range).

 
There were no adverse events considered related to rFVIIa.


    Discussion
 Top
 Footnotes
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In our randomized, double-blind, placebo-controlled trial, rFVIIa at a dose of 90 µg kg–1 given to patients undergoing pelvic–acetabular surgery did not decrease the total volume of perioperative blood loss compared with placebo. Furthermore, there were no statistically significant differences in the total transfusion requirement, the number of patients requiring allogeneic blood and other secondary outcomes between the rFVIIa and placebo groups.

Previous publications have shown the haemostatic efficacy of rFVIIa in patients with impaired haemostasis undergoing orthopaedic surgery, mainly arthroplasty.1618 Unlike those patient groups, the patients in our study had normal haemostatic function, evident by the normal values of preoperative PT, APTT and fibrinogen concentration. The use of rFVIIa prophylactically at the start of surgery did not significantly provide additional haemostasis in our patient group.

In contrast to our study, a randomized study has shown that in patients undergoing retropubic transabdominal prostatectomy, rFVIIa at a dose of 40 µg kg–1 given at an early phase of the surgery reduces perioperative blood loss and eliminates the need for blood transfusion.19 The patients in this study also had normal haemostatic function. The discrepancy in the efficacy of rFVIIa between the previous study and our study may be partly explained by a number of differences. In this study, we used salvaged RBC, which were not used in the previous study. In addition, the patients in the previous study were in a higher age group than those in our study (60 vs 40 yr). In elderly patients, the tissue surrounding blood vessels is loose, and this may decrease the haemostatic function of the vascular compartment. Furthermore, the difference in the nature of the two surgical procedures may also account for the discrepancy in rFVIIa efficacy. The prostate gland is a soft tissue surrounded by venous plexus. This, combined with the anatomical complexity of the prostate gland, leads to a relatively higher risk of massive perioperative blood loss in prostatectomy compared with orthopaedic surgery. Furthermore, in patients undergoing prostatectomy, urokinase in the urine can diffuse into the operative site to dissolve the formed haemostatic plugs, resulting in impaired local haemostasis.20 In contrast, the initial severe trauma which caused fractures in the patients in our study may induce the release of inflammatory mediators which can activate the coagulation system. Hence, the patients in our study are considered hypercoagulable, requiring prophylactic anticoagulants.

This study has used a traditional method to measure perioperative blood loss and a more recent method to calculate the blood loss. The measured blood loss was the sum of accurate weighing of swabs and measurement of loss in drains. The measured blood loss in the control group was lower than that in the historical data used to calculate the sample size (1535 vs 2818 ml). In contrast, the calculated blood loss was close to the historical data (2787 vs 2818 ml), suggesting that the power calculation on which the sample size was based was accurate. The measurement of the precise volume of perioperative blood loss in orthopaedic surgery is difficult and the potential inaccuracy of the estimated perioperative blood loss should be taken into consideration. It has been suggested that calculated blood loss might be more reliable.15 The results produced by the Rosencher method combined with the measured blood loss at the time of surgery added to the loss measured in the drains postoperatively suggest that at the time of surgery there was a slightly greater blood loss in the group receiving rFVIIa but that this was reversed after surgery, the control group losing more blood in the period after the end of surgery and up to 48 h. This would imply that the control group had a greater postoperative loss in and around the wound but not sufficient to manifest itself in the wound drain. This could possibly be due to the rFVIIa producing a more stable clot and better haemostasis at the end of surgery, and this is worth further investigation.

The proportion of patients requiring allogeneic RBC transfusion was slightly lower in the rFVIIa group compared with the placebo group (46 vs 67%). The difference did not reach statistical significance. A similar trend towards the reduction of allogeneic RBC requirement was also seen in a previous randomized control trial in non-cirrhotic patients undergoing partial hepatectomy, 25% of patients in the rFVIIa group and 37% of patients in the placebo group being transfused.21

Patients with pelvic–acetabular fractures are considered at risk of thromboembolic events and therefore require prophylactic anticoagulant both before and after surgery. The administration of a procoagulant agent such as rFVIIa to such patients might raise concerns that patients would be exposed to a higher risk of thromboembolism. However, we did not observe any adverse event, in particular thromboembolic events, in the rFVIIa group. It is noteworthy that all patients in the trial received prophylactic anticoagulation with LMWH and warfarin before and after surgery.

In conclusion, the early prophylactic use of rFVIIa does not decrease the total volume of perioperative blood loss in patients with normal haemostasis undergoing major pelvic–acetabular fracture reconstruction surgery.


    Acknowledgments
 
We would like to thank Martin Bircher, Adrian Day and the staff at St George's hospital for all their help and cooperation in the trial, and Pranee Krailadsiri, Novo Nordisk Health Care AG, Switzerland, for assisting in the preparation of the manuscript.


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{dagger} This article is accompanied by the Editorial. Back

{ddagger} Declaration of interest. R. M. Grounds has worked in the past as a consultant for Novo Nordisk and has lectured at symposiums organized by Novo Nordisk. Novo Nordisk has given an unrestricted educational grant to St George's Hospital Special Trustee's. The trial was funded by Novo Nordisk, UK. Back


    References
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 Footnotes
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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17 Tobias JD. Synthetic factor VIIa to treat dilutional coagulopathy during posterior spinal fusion in two children. Anesthesiology 2002; 96: 1522–5[CrossRef][ISI][Medline]

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