1 Department of Anaesthesia and 2 Department of Haematology, Southampton University Hospitals, Tremona Road, Southampton SO16 6YD, UK
* Corresponding author. E-mail: ravi.gill{at}suht.swest.nhs.uk
Accepted for publication July 1, 2005.
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Abstract |
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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 0.070.9; 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 non-coronary cardiac surgery without causing adverse events.
Keywords: blood, coagulation, rFVIIa ; blood, transfusion ; surgery, cardiovascular
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Introduction |
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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.814
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.1517 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.
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Materials and methods |
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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 µg 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 µg 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 cell-salvage 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.
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Primary endpoints were the number of patients receiving any allogeneic transfusion, the total units of allogeneic red 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 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 µg 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 ShapiroWilk W test. Parametric data were analysed with analysis of variance (ANOVA), and non-parametric data were analysed with the KruskalWallis 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
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Results |
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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 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 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.
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Discussion |
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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 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 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 µg kg1) than in the present study. The dose of 90 µg 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 µg 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.
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Acknowledgments |
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Footnotes |
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References |
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