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Eur J Cardiothorac Surg 2008;33:64-71. doi:10.1016/j.ejcts.2007.10.004
Copyright © 2008, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
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Treatment of refractory bleeding after cardiac operations with low-dose recombinant activated factor VII (NovoSeven®): a propensity score analysis

Sandro Gelsominoa,*, Roberto Lorussob, Stefano Romagnolic, Sergio Bevilacquaa, Giuseppe De Ciccob, Giuseppe Billèc, Pierluigi Stefànoc, Gian Franco Gensinid

a Experimental Surgery Unit, Department of Heart and Vessels, Careggi Hospital, Florence, Italy
b Cardiac Surgery Unit, Civic Hospital, Brescia, Italy
c Cardiac Surgery Unit, Department of Heart and Vessels, Careggi Hospital, Florence, Italy
d University of Florence, Florence, Italy

Received 19 July 2007; received in revised form 6 October 2007; accepted 9 October 2007.

* Corresponding author. Address: Experimental Surgery Unit, Department of Heart and Vessels, Careggi Hospital, Viale Morgagni 85, 50134 Florence, Italy. Tel.: +39 055 794 7467; fax: +39 055 794 7628. (Email: sandro.gelsomino{at}libero.it).


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Comment
 5. Conclusions
 Appendix A
 References
 
Background: Recombinant activated factor VII (rFVIIa) has been increasingly used to stop life-threatening bleeding following cardiac operations. Nonetheless, the issue of dosing, given the expense and potential for thrombotic complications, is still of major concern. We report our experience with small-dose rFVIIa in patients with refractory bleeding after cardiac surgery. Methods and results: From September 2005 to June 2007, 40 patients (mean age 70.1 ± 9.2 years, 52.5 males) received a low dose of rFVIIa (median: 18 µg/kg, interquartile range: 9–16 µg/kg) for refractory bleeding after cardiac surgery. Forty propensity score-based greedy matched controls were compared to the study group. Low dose of rFVIIa significantly reduced the 24-h blood loss: 1610 ml [ 1285–1800 ml] versus 3171 ml [2725–3760 ml] in the study and control groups, respectively (p < 0.001). Thus, hourly bleeding was 51.1 ml [34.7–65.4 ml] in patients receiving rFVIIa and 196.2 ml/h [142.1–202.9 ml] in controls (p < 0.001). Furthermore, patients receiving rFVIIa showed a lower length of stay in the intensive care unit (p < 0.001) and shorter mechanical ventilation time (p < 0.001). In addition, the use of rFVIIa was associated with reduction of transfusion requirements of red blood cells, fresh frozen plasma and platelets (all, p < 0.001). Finally, treated patients showed improved hemostasis with rapid normalization of coagulation variables (partial thromboplastin time, international normalized ratio, platelet count, p < 0.001). In contrast, activated prothrombin time and fibrinogen did not differ between groups (p = ns). No thromboembolic-related event was detected in our cohort. Conclusions: In our experience low-dose rFVIIa was associated with reduced blood loss, improvement of coagulation variables and decreased need for transfusions. Our findings need to be confirmed by further larger studies.

Key Words: Hemorrhage • Plasma • Platelet-derived factors • Platelets


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Comment
 5. Conclusions
 Appendix A
 References
 
There has recently been a great deal of interest in the use of recombinant activated factor VII (rFVIIa, NovoSeven, NovoNordisk, Bagsvaerd, Denmark), for control of refractory bleeding after cardiac operations [1]. Recombinant activated factor VII was licensed in 1999 by the United States Food and Drug Administration (FDA) for its use in the management of patients with hemophilia with inhibitors to factor VIII or IX [2]. In 2005 it was further approved for surgical procedures in hemophiliacs and for patients with factor VII deficiency [3]. Then, the off-label use of this agent was reported in patients with life-threatening bleeding after trauma or major abdominal surgery [4]. However, the efficacy in reducing blood loss and transfusion requirements in patients undergoing cardiac surgery is debated yet. Furthermore, the issue of dosing (given the expense and potential for thrombotic complications) is still of major concern.

We report our experience with small-dose rFVIIa used as rescue therapy in patients with refractory bleeding after cardiac surgery.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Comment
 5. Conclusions
 Appendix A
 References
 
2.1 Patients and definitions
Starting from September 2005 to June 2007, 2398 consecutive patients underwent cardiac surgery at our institution (Cardiac Surgery, Careggi Hospital, Florence, IT). Of them, 298 (12.4%) suffered from significant bleeding defined as bleeding that compromises hemodynamics and/or bleeding ≥500 ml/h during the first postoperative hour, or bleeding ≥300 ml/h for three consecutive hours after chest closure, or bleeding ≥1200 ml/h after the fifth postoperative hour [5]. Data were collected by research assistants who were blinded to the nature of the study and were analyzed by a surgeon (GB) and an anesthesiologist (SB) who identified 228 patients with refractory bleeding (Fig. 1 ). Blood loss was considered refractory when a surgical bleeding source was excluded at surgical re-exploration after a complete transfusion protocol in patients who received a second complete transfusion protocol.


Figure 1
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  		Fig. 1. Study design.

 
Among patients with refractory bleeding, 17.5% (n = 40) were treated with small-dose rFVIIa as rescue therapy. The final decision to employ rFVIIa was made by the attending anesthesiologist and it was based on a risk/benefit evaluation and/or his/her personal preferences. No formal exclusion criteria were applied.

A small-dose (1.2 mg) rFVIIa was given as a slow intravenous bolus. This dose was chosen empirically after examination of published reports [1]. Doses ranged from 10.9 to 19.3 µg/kg (median: 18 µg/kg; interquartile range: 9–16 µg/kg). The infusion was repeated in case of persistent bleeding defined as bleeding ≥150 ml/h for three consecutive hours after the treatment. If bleeding persisted patients underwent further surgical re-exploration.

2.2 Institutional protocol
Before the initiation of cardiopulmonary bypass (CPB), all patients received porcine heparin at an initial dose of 300 U/kg, injected IV before cannulation of the aorta. An additional dose of 5000 U of heparin is administered when the kaolin activated clotting time (ACT) is ≤400 s [6]. An additional dose of 2500 U was given if the ACT declined above 300 s. After complete weaning from CPB heparin is neutralized by endovenous infusion of protamine hydrochloride at the dose of 0.6 mg per 100 U of heparin administered [6]. Heparin neutralization is considered adequate if post-protamine ACT value is within 10% of the pre-heparin value.

Red blood cells (RBCs) are given to maintain the hemoglobin concentration ≥7 g/dl during CPB. All patients receive antifibrinolytics (10 mg/kg bolus of Tranexamic acid followed by an infusion of 1 mg kg–1 hm+ for the duration of the procedure and, in case of reintervention or acute aortic dissection, 2.0 million KIU aprotinin before CPB followed by 2.0 million KIU in CPB-prime and 500,000 KIU/h for the duration of the procedure).

All patients with refractory bleeding were operated on by three surgeons. The intensive care unit (ICU) staff (physicians) was the same and anesthetic management was identical in the entire cohort. Surgery was performed through a median sternotomy on CPB with antegrade/retrograde cold blood cardioplegia. The lowest temperature achieved was 34 °C (21 °C in patients who underwent deep hypothermic circulatory arrest).

Subjects with significant bleeding undergo 1000 IU of prothrombin complex concentrates (PCC) [7] associated to the following transfusion protocol: [8,9]

- Red blood cells (RBCs) to maintain the hemoglobin concentration ≥9 g/dl during the postoperative period.
- 10–15 ml/kg of fresh frozen plasma (FFP) when prothrombin time (PT) >1.5 times the control values.
- One unit of pooled PLT concentrates/10 kg body weight.

2.3 End points
End points were measured in traded patients and controls following the second transfusional protocol (T 0). Primary outcome was the effectiveness in terms of blood loss, transfusion requirements, changes in coagulation laboratory findings and clinical findings (death, complications, time of mechanical ventilation [MV] and intensive care unit length of stay [ICU LoS]). Blood loss was explored either as hourly bleeding or as 1-, 3-, 5-, 10-, 15-, 20-, or 24-h bleeding. The need for RBCs, FFP, and PLT transfusion in study patients after the administration of rFVIIa was compared with controls. Laboratory evaluation included partial thromboplastin time (PT), international normalized ratio (INR), activated prothrombin time (aPTT), fibrinogen (FBG) and platelet (PLT) count.

Screening for thromboembolic events was performed by physical examination. If a thromboembolic complication was suspected, color Doppler sonography, transesophageal echocardiography, computed tomography scan and laboratory tests were performed to confirm the diagnosis.

2.4 Ethical issues
Following the World Medical Association guidelines concerning ethical principles for medical research involving human subjects [11], the Institutional Ethics Board approved the study. Our institution approved the use of rFVIIa in the setting of life-threatening post-cardiac surgery hemorrhage. Specific patient or patient family consent of this use was not obtained because of the emergency nature of the circumstance, although all patients had given informed consent to the procedure and they were aware that hemorrhage was a possible and significant complication. Nonetheless, ethics board approval was obtained to review records of patients receiving rFVIIa as well as the records of all patients undergoing cardiac surgery to identify controls.

The authors had full access to the data and take responsibility for its integrity. All authors have read and agreed to the manuscript as written.

2.5 Statistical analysis
Pre-matched baseline characteristics of patients with refractory bleeding are shown in Table 1 . Data were compared with Pearson chi-square and Wilcoxon rank-sum test for categorical and continuous variables, respectively.


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  		Table 1 Prematching characteristics
 
To allow an unbiased comparison between patients with refractory bleeding receiving rFVIIa and controls, the propensity score analysis was employed [10].

The logistic procedure allowed us to calculate the predicted probability (propensity score) of receiving the rFVIIa [11]. Variables considered for inclusion in this model included: endocarditis, congestive heart failure, baseline hemoglobin, baseline platelets count, baseline PT, baseline INR, baseline aPTT, baseline FBG, baseline creatinine, antiplatelet therapy, anticoagulation therapy, urgency/emergency surgery, redo surgery, complex operation (ascending aorta and/or arch operation, multiple valve or associated valve and coronary artery bypass grafting procedures), CPB time, hypothermic circulatory arrest (HCA time), bleeding at T 0, Nadir hematocrit (Hct) during CPB, use of aprotinin (tranexamic acid was received by all patients) and blood products transfused either in the intensive care unit (ICU) or in the operative room (OR) before T 0. The model's reliability and its predictive ability were tested with Hosmer–Lemeshow (HL) goodness-of-fit test and the C-index, respectively [12]. This model did not show evidence of lack of fit based on the HL statistic (p = 0.27) and confirmed high discriminative ability (C-test = 0.94).

The SAS Greedy 5 -> 1digit match macro was used to identify a matched control for each treated patient [13] according to their propensity score.1

Adequacy of covariate balance in the matched sample was assessed with Mc Nemar or Wilcoxon's signed rank test, which were also employed to assess the differences between treated patients and matched controls for outcome and adverse events as well as for pre–post comparison within groups.

Coagulation measures were presented as median and interquartile range. The propensity score-based greedy matching algorithm successfully matched all the 40 treated patients. Adequacy of covariate balance in the matched sample is shown in Table 2 .


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  		Table 2 Greedy 5 -> 1 digit match
 
A sensitivity analysis was performed to assess the sensitivity of the findings of this case–control study to the assumption about unmeasured confounders using the following formula [14]:


Formula

where R and R* are, respectively, the apparent and true relative risks of bleeding associated with the treatment. A is the adjustment factor. {Gamma} 0 and {Gamma} 1 are the relative risks associated with the unmeasured confounder and P 0 and P 1 the prevalences of the unmeasured confounder in treated versus control patients, respectively.

In Appendix 1 the point and the interval estimates for the odds ratio of interest after adjustment for an unmeasured confounder are displayed.

Based on 24-h blood loss as a primary outcome, this study had 80% power to detect a 10 ml difference in 24-h bleeding.

We considered a p-value of <0.05 to be statistically significant. Analyses were performed using SAS Statistical Package, release 9.1 (SAS Institute, Cary, NC).


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Comment
 5. Conclusions
 Appendix A
 References
 
3.1 Blood loss and transfusions requirement
Blood loss after rVIIa was significantly lower than before the therapy (p < 0.001). Median 24-h blood loss (Fig. 2A) was 1610 ml [interquartile range: 1285–1800 ml] and 3171 ml [2725–3760 ml] in the study and control groups, respectively (p < 0.001). Thus, hourly bleeding was 51.1 ml [34.7–65.4 ml] in patients receiving rFVIIa and 196.2 ml/h [142.1–202.9 ml] in controls (p < 0.001). A further comparison of the degree of bleeding in the two groups (Fig. 2B) showed that it was reduced significantly in the study group at 3 h (p < 0.001), 15 h (p < 0.001), 20 h (p = 0.02), and 24 h, remaining unchanged at 5 h and 10 h (p = ns). In contrast, in controls, blood loss did not significantly change at 3, 5, 10, 15, 20, and 24 h and it was, at all times, constantly higher than in the study group (p < 0.001). The result of sensitivity analysis (Appendix 1) strongly support the conclusion that rVIIa decreased the risk of persistent bleeding.


Figure 2
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  		Fig. 2. (A) Blood loss in study and control groups starting from T 0 (see text). Data are presented as medians (dotted lines) and 25th and 75th percentiles (solid lines). (B) Blood loss/h. Data are presented as median [interquartile range]. *Significance versus study group.

 
Transfusion requirements for RBCs (p < 0.001), FFP (p < 0.001) and PLTs (p < 0.001) were lower in the study group patients than in controls (Fig. 3A–C).


Figure 3
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  		Fig. 3. Units of red blood cells (A), fresh frozen plasma (B) and platelets (C) transfused in study and control groups starting from T 0 (see text). Data are presented as median [interquartile range].

 
Blood product usage after rVIIa therapy was significantly lower than before it (p < 0.001).

3.2 Coagulation laboratory findings
Following the administration of rFVIIa, PT increased significantly only in the study group (p < 0.001, Table 3 ). The INR showed a significant reduction in both groups (p < 0.001 and p = 0.03 in the study and matched controls, respectively) and it was significantly lower in the study group (p < 0.001). The aPTT improved in treated patients (p = 0.001) and controls (p = 0.03) without significant difference between the groups. Contrastingly, FBG increased significantly only in patients receiving rFVIIa (p < 0.001). Finally, the platelet count increased in the study group (p < 0.001) while it reduced significantly in controls (p < 0.001).


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  		Table 3 Coagulation findings
 
3.3 Clinical outcomes
Clinical outcomes are shown in Table 4 . Death occurred in 3 patients (7.5%) in the control group versus 2 (5.0%) in the study group (p > 0.9). Complication rates were 20.0% (n = 8) and 17.5% (n = 7) in the study and control groups, respectively (p > 0.9). Time of MV (p < 0.001) as well as ICU LoS (p < 0.001) was significantly lower in patients receiving rFVIIa than in controls.


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  		Table 4 Clinical outcome
 
Thirty-five patients in the control group (87.5%) underwent a second surgical re-exploration for persistent bleeding and in only 2 cases was a surgical bleeding site identified. In contrast, 3 patients (7.5%) receiving rFVIIa ({chi} 2 = 8.3, p < 0.001) underwent second surgical re-exploration due to bleeding persisting after a second dose of VIIa. A surgical source of blood loss was identified in all these 3 patients.

Two treated patients had postoperative stroke; in both a predisposing factor for cerebrovascular accident was clearly identified: the first patient had preoperative transient ischemic attacks followed by stroke occurring 8 months before surgery, resulting in complete functional recovery. The second underwent prolonged deep hypothermic circulatory arrest with postoperative hypoperfusion resulting in multiple ischemic injures shown by postoperative CT scan. In the remaining patients, the use of rFVIIa caused no thromboembolic complication at clinical examination, laboratory tests, and transesophageal echocardiography.


   4. Comment
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Comment
5. Conclusions
 Appendix A
 References
 
Undetermined effectiveness, safety and high cost are the reasons why rFVIIa is mainly used as the very last therapeutic option in absence of response to transfusion and conventional procoagulant agents. To our knowledge, only 4 studies have reported the utilization of rFVIIa as primary therapy [15] or as a prophylactic hemostatic agent [16]. The aim of this study was to determine the effectiveness of rFVIIa employed at very low doses in reducing blood loss and transfusion requirements after cardiac surgery. To assess the efficacy of VIIa recombinant, we compared the study group with 40 propensity score-based greedy matched controls.

The optimal dosage of rFVIIa in cardiac surgery remains unclear and satisfactory coagulation was yielded with doses ranging from 13 to 192 µg/kg [17]. Furthermore, recurrent injections were sometimes necessary due to the short half-life of rFVIIa [18]. In the present study, a small dose of rVIIa (10.9–19.3 µg/kg [median: 18 µg/kg, interquartile range: 9–16 µg/kg]) was employed as rescue therapy in life-threatening post-cardiac surgery refractory hemorrhage. A single dose of rFVIIa significantly reduced the postoperative bleeding in 92.5% of patients. Three patients showed persistent bleeding after a second dose and they underwent surgical re-exploration, which showed a surgical site responsible for blood loss in all. In contrast, 35 patients in the control group (87.5%) underwent a second surgical re-exploration for persistent bleeding and in only two cases was a surgical bleeding site identified. Furthermore, according to Karkouti et al. [18], patients receiving rFVIIa showed a lower ICU LoS and shorter time of mechanical ventilation. In addition, the use of rFVIIa was associated with a reduction of RBCs, FFP, and PLT transfusion requirements. Finally, treated patients showed improved hemostasis with rapid normalization of coagulation variables: PT was increased in patients who received rFVIIa (p < 0.001), and, accordingly, INR was significantly reduced in the study group (p < 0.001). Finally, PLT count was significantly higher in patients treated with rFVIIa (p < 0.001), whereas aPTT and FBG did not differ between groups.

4.1 Thrombotic risk
Recombinant factor VIIa is a drug generally well tolerated. Nonetheless, the occurrence of thrombosis is of primary concern with the administration of rFVIIa [19]. The tissue factor (TF) is localized in the deeper layers of vascular walls and, normally, it is not exposed to the circulating blood. TF binds to FVII at a site of vascular injury and TF–VIIa complex allows the conversion of FVII to FVIIa, activates factors IX and X and enhances thrombin generation. Cardiopulmonary bypass (CPB) may up-regulate TF systematically as well as at the site of surgical injury [20] and this may lead to systemic or local thrombosis.

Nevertheless, despite the use of rFVIIa in 304 cardiac surgery patients with refractory hemorrhage, the incidence of this serious adverse event remains very low (4.6%) [1]. This can be theoretically explained by the presence of some potential protective mechanisms which work against thrombotic complications in these patients: (1) the plasma concentration of tissue factor pathway inhibitor (TFPI), a strong inhibitor of the enzymatic activity of the TF–FVIIa complex, rises, still remaining high at the end of CPB; [21] (2) antifibrinolytic agents are normally used in conjunction with rFVIIa. Tranexamic acid inhibits binding of plasminogen to fibrin and aprotinin is a non-specific inhibitor of serine proteases, although its relative affinity is highest for plasmin [22]. However, even though published data have shown a good level of safety in cardiac surgery patients, these subjects must be considered at high risk for thrombotic complications [19]. Particularly, the influence of rFVIIa on graft patency after coronary artery bypass grafting (CABG) is still unknown and many authors believe the use of rFVIIa to be contraindicated in these subjects. In the present report, among patients in the study group, 20 (50%) underwent isolated or combined CABG and they did not show either clinical, or electrocardiographic and echocardiographic signs of graft occlusion. Two study patients had postoperative stroke and in both a predisposing factor was clearly identified; in the remaining patients no thromboembolic complication was detected.

4.2 Study limitations
Our study findings should be viewed in light of some inherent limitations. This study was neither randomized nor prospective. Nonetheless, in the absence of randomization, we employed the propensity score to ensure an unbiased comparison for treatment effectiveness. However, the propensity score matching can only adjust for observed potential confounders, thus we employed a sensitivity analysis for persistent bleeding to account for unmeasured confounders.

PCC has been shown to be more effective than rVIIa to reverse melagatran anticoagulation [23] and coumarin anticoagulation [24] and that manipulation of prothrombin concentration with PCC significantly impacts the effectiveness of rVIIa in a cell model of hemophilia [25] suggesting that the combination of drugs may offer advantages over the use of rVIIa alone and this could explain why such minor doses of rVIIa were, in our experience, effective.

4.3 Strength of the study
The patients in our study were treated in a single institution according to standardized clinical guidelines. Moreover, our patient population was more homogeneous than in other published studies. Additionally, the dose of rFVIIa given and the timing of administration were more standardized than in other reports. Finally, the dosage employed was, as far as we know, the lowest reported in the English literature.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Comment
 5. Conclusions
Appendix A
 References
 
Even with the above-mentioned limitations, we can conclude that low doses resulted to be effective in refractory hemorrhage associated with cardiac surgery. Further larger, randomized, multicenter, controlled trials are necessary to confirm the efficacy of rFVIIa in this setting.


   Appendix A
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Comment
 5. Conclusions
 Appendix A
References
 
Sensitivity analysis


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   Acknowledgments
 
We gratefully acknowledge Dr Judith Wilson for the English revision of the manuscript. We thank Dr Orlando Parise for the statistical analysis.


   Footnotes
 
1 http://www2.sas.com/proceedings, last access 20/06/2007. Back


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Comment
 5. Conclusions
 Appendix A
 References
 

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ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
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