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Ann Thorac Surg 2007;83:707-714
© 2007 The Society of Thoracic Surgeons

Reviews

Recombinant Activated Factor VII in Cardiac Surgery: A Systematic Review

Oliver Warren, MRCS, Kaushik Mandal, MS, MRCS, Vassilis Hadjianastassiou, MD, Lisa Knowlton, BSc (Hons), Sukhmeet Panesar, BSc (Hons), Kokotsakis John, MD, Ara Darzi, FMedSci, KBE, Thanos Athanasiou, MD, PhD*

Department of BioSurgery and Surgical Technology, Imperial College Faculty of Medicine, St. Mary’s Hospital, London, United Kingdom

* Address correspondence to Dr Athanasiou, Department of BioSurgery and Surgical Technology, Imperial College Faculty of Medicine, 10th Floor QEQM Building, St. Mary’s Hospital, London, W2 1NY United Kingdom. (Email: tathan5253{at}aol.com).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 References
 
Postoperative hemorrhage is a common complication in cardiac surgery, and it is associated with a considerable increase in morbidity, mortality, and cost. Recombinant activated factor VII (rFVIIa) is an emerging hemostatic agent, increasingly used in cardiac surgery. This article systematically reviews the evidence regarding the efficacy, safety, and cost of rFVIIa in this setting. Although definitive evidence from randomized controlled trials is lacking, the use of rFVIIa in patients experiencing refractory postoperative hemorrhage seems promising and relatively safe. However further research is required to definitively establish its clinical utility in the postoperative cardiac patient.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 References
 
Cardiothoracic surgery utilizes 10% to 15% of all the blood donated in the United Kingdom [1]. Despite a variety of different preventative techniques [2], blood product usage remains in the range of 70% to 80% in complex cardiac surgical cases, and the incidence of excessive postoperative bleeding approaches 11% [3]. The search for strategies to reduce severe postoperative hemorrhage therefore continues.

Recombinant factor VIIa (rFVIIa) (NovoSeven; Novo Nordisk, Bagsvaerd, Denmark) was first used to decrease hemorrhage in patients with hemophilia A or B with inhibitors (neutralizing auto-antibodies) to factor VIII or IX [4]. In 1999 the United States Food and Drug Administration (FDA) licensed rFVIIa for this purpose [5], and in 2005 it was further approved for surgical procedures in the same patient group, and for patients with factor VII (FVII) deficiency [6]. The medical literature increasingly describes off-license rFVIIa use to control hemorrhage in other patient groups [7–9].

Although off-label use of rFVIIa has been reported in cardiac surgery, this has been published predominantly as case reports or series [10–16]. Where reviews have been performed, they have been nonsystematic and incomplete [17], or have not focused specifically on cardiac patients [9]. In this article, we systematically review all the available evidence on the efficacy, dosage, safety, and cost implications of rFVIIa use in cardiac surgery.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 References
 
Relatively little is known about the molecular mechanisms by which rFVIIa induces the formation of a stable hemostatic plug. Most researchers in the field agree that rFVIIa has no direct effect on hemostatic plug formation, but exerts an effect by enhancing thrombin generation at sites of tissue injury. However, controversy exists regarding the mechanisms by which this occurs, specifically the role and source of the protein Tissue Factor (TF).

When vessel injury occurs in normal subjects, subendothelial cells that express TF are exposed to the blood. Subsequently TF binds to and activates FVII. The resulting TF-FVIIa complex catalyzes the conversion of factor X into its active form (Xa) leading to thrombin formation and platelet activation. This creates a surface that supports the binding of coagulation factors and thereby facilitates the full thrombin burst necessary for hemostasis. However, TF expression is not restricted to the subendothelium. Neutrophils and monocytes have been shown to produce and present TF when stimulated by inflammatory cytokines [18, 19]. In recent years controversy has arisen related to the presence, concentration, and function of TF within circulating blood [20]. Several groups of investigators have reported the presence of physiologically active blood-borne TF [21–23], whereas others have refuted its existence or for it to be physiologically possible in healthy individuals [24, 25]. Blood-borne TF has been reported as being located on blood cells, being an undefined mixture of pro-coagulant microparticles (0.1 to 1 µm) or being soluble pro-coagulant TF fragments [26–28]. Blood-borne TF in combination with activated monocytes may activate FVII in cardiac surgical patients more than when combined with activated platelets [21, 29].

The exact role of TF in the effect of rFVIIa requires further elucidation. Knowledge of the normal hemostatic process, plus the fact that rFVIIa seems to enhance coagulation at sites of tissue injury, led to the hypothesis that rFVIIa acts through a TF-dependent mechanism [30–32]. Although this is supported by various studies using different models [33], the high plasma concentrations of rFVIIa required to induce hemostasis suggest that TF-dependent activation can not be the sole mechanism. It has been shown that rFVIIa is able to directly activate factor X on phospholipid vesicles, activated platelets or monocytes independently of TF [34–36], although TF-independent generation of thrombin is much less efficient and has not been replicated by all groups [37].

In reality it seems likely that rFVIIA functions through a combination of TF-dependent and TF-independent pathways, and that TF-rFVIIa interaction is not solely limited to the subendothelium.

Literature Search
Medline, Embase, Ovid and Cochrane database searches were performed to identify all studies concerned with the use of rFVIIa in cardiac surgery. The following MeSH headings were used: "recombinant factor VIIa," "rFVIIa," and "cardiac," "hemorrhage," "cardiopulmonary," "outcomes," and "surgery." The "related articles" function was utilized to broaden the search, and all abstracts, studies, and citations were scanned and reviewed. Based on the title and abstract of the publication, we retrieved articles containing clinical data on the use of rFVIIa. References of the articles acquired were also searched manually. No language restrictions were made. Laboratory and animal studies were excluded. The latest date for this search was July 1, 2006.

Data Extraction and Validation of Studies
Two reviewers (OW and KM) independently extracted the following data from each study: first author, year of publication, study population characteristics, study design, number of subjects, procedure type, pathology, and the following outcomes of interest: dosage, effect on blood loss, adverse events (stroke, myocardial infarction and other thromboembolic effects), and mortality. Articles that studied the effect of rFVIIa on a mixed cohort of patients (eg, those in intensive care units) were also studied, and data for any cardiac patients involved in those studies was extracted.

Articles were classified as case reports or series, retrospective chart (or database) reviews, and clinical studies. The clinical studies were further classified according to whether or not they were retrospective or prospective (in which case they must have a pre-defined outcome to be assessed), and whether or not they were comparative. The studies were too heterogeneous to be combined for a formal meta-analysis, and therefore a systematic synthesis was undertaken.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 References
 
Study Identification
Figure 1 outlines the systematic search strategy and results. Fifty-two articles and their references were investigated in full. This led to the exclusion of 8 studies and provided a further 3 studies for evaluation. One report [38] was excluded due to duplication of cases from a report published by the same author 2 years earlier [10]. This left 46 articles, 40 focused on purely cardiac surgical patients, and 6 were mixed populations, containing some cardiac patients. Two articles were prospective, double-blind randomized controlled trials [39, 40] and another four were cohort studies with a control group [14, 41–43]. These six comparative studies are summarized in Table 1. Of the remaining 40 publications, 8% were cohort studies, 32% were retrospective database reviews, and 60% were case reports or series. The aggregate data extracted from all 46 articles is presented in Table 2.


Figure 1
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  		Fig 1. Systematic search strategy.

 

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  		Table 1. Comparative Studies Reporting the Administration of rFVIIa in Cardiac Surgical Patients
 

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  		Table 2. Data Synthesis From All Reports
 
Case Mix and Patient Demographics
The 46 articles reported on 501 patients, of whom 146 were matched controls, or received a placebo (see Table 2). We identified 355 cardiac patients within the literature who have received rFVIIa. In the vast majority (86%) the indication was refractory bleeding. The other 14% received prophylactic rFVIIa as participants within the two randomized control trials [39, 40] (see Table 1). Although the majority (77%) of the 355 treated patients were adult, a significant proportion (23%) were pediatric cases (from neonates [40, 44] to older children [14, 45]). Within the paediatric subgroup, 53% of patients received rFVIIa prophylactically. The majority of pediatric cases were atrial, atrioventricular, or ventricular septal defect repairs (32%), or surgery for correction of transposition of the great vessels (26%), tetralogy of Fallot (18%), or other congenital abnormalities (30%). Only one pediatric case was a re-do procedure. The range of procedures performed on rFVIIa-treated adult patients is relatively comprehensive, but most frequently were coronary artery bypass grafting (22%), valve replacements (28%), or a combination of the two (16%). A significant proportion of the cases (19%) were re-do procedures. Only four coronary artery bypass procedures were performed off-pump, split equally between two studies [43, 46].

Of the 355 treated patients, only 6% had a declared degree of impaired hemostasis prior to surgery (eg, were on an anticoagulant, had liver disease or a known coagulopathy). However, in a further 28% of patients the absence or presence of this risk factor for hemorrhage was not stated in the text.

We searched all of the studies to find any potential conflicts of interest. Five studies declared that one or more of the authors had a financial arrangement with the supplier of rFVIIa [10, 14, 41, 47, 48]. These studies were not uniformly positive in their reporting of the effects of rFVIIa.

Recombinant FVIIa in Refractory Hemorrhage
To aid data synthesis, we arbitrarily chose three dosing levels of rFVIIa in refractory hemorrhage (see Table 3). In cases in which patients received more than one dose, we calculated their cumulative dose per kg body weight. The range of rFVIIa administered as a single dose was broad (11.1 to 180 µg/kg). The majority of adult (75%) and pediatric patients (61%) received total doses less than or equal to 90 µg/kg. One group used a low dose of 11.1 to 25.1 µg/kg and reported a positive impact on blood loss [43], and similar effects at low dose are reported elsewhere [10, 44, 49]. Others gave very high cumulative doses (>400 µg/kg) during a time span of a number of hours [45, 50]. The frequency with which rFVIIa is administered is highly variable. Some studies have used only a single bolus [14], and others have used repeated doses at varied intervals [41, 42], with patients sometimes only receiving a second dose if bleeding failed to stop [51–53]. A factor that affected the dosing regimen of many of the authors is that rFVIIa is manufactured in vials of 1.2, 2.4, and 4.8 mg [54], and due to the expense of every vial (approaching $1/µg), many centers reporting retrospective chart reviews or case series used "best-fit" dosing regimes to avoid opening more vials than necessary [49, 54, 55]. In larger prospective studies, the dose was more precise, but it still varied significantly [14, 41].


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  		Table 3. Dosing and Adverse Events in Refractory Hemorrhage Cohort
 
In two of the studies reporting its use in refractory hemorrhage, rFVIIa was given as the primary therapy before any blood product replacement. In one study this was due to the patients’ religious beliefs [49] and the other was performed in a developing country without any blood transfusion service [14]. Both these studies reported rFVIIa to decrease chest tube drainage. In all other studies, rFVIIa was administered as a rescue therapy when all other established treatments seemed to have failed, including re-exploration on occasion [54, 56, 57]. Although these reports are too heterogeneous to allow clear delineation of how many patients received which blood products, it is possible to state that all studies administered a combination of blood, platelets, and clotting factors, along with varied anti-fibrinolytics. Most authors use terms such as "exhaustive attempts to correct" or "intractable bleeding" prior to rFVIIa administration [42, 43, 56, 58].

The use of rFVIIa as rescue therapy has met with mixed results. Although the majority of noncomparative articles reported a reduction in blood loss, either as witnessed by the surgeon [56], decreased chest drain output [49, 54, 59, 60], or decreased need for further blood products [50, 61], there is obviously an inherent publication bias in such reports. There are four comparative studies performed on FVIIa in refractory hemorrhage (see Table 1). Romagnoli and colleagues [43] assessed rFVIIa as a rescue therapy only at the end of a strict step-by-step transfusion protocol. They found significantly reduced blood loss, transfusion requirements and intensive care unit stays in the study group when compared with case-matched controls [43], findings replicated partly by Karkouti and colleagues [42]. Tobias and collegues [14] witnessed a reduction in chest tube bleeding in hemorrhaging pediatric patients given rFVIIa compared with nonbleeding controls [14]. Von Heymann and colleagues [41] found no significant difference in blood loss, blood product requirements, or chest tube bleeding in treated patients.

The main concern with the administration of rFVIIa is the potential for inappropriate thrombosis. Cardiopulmonary bypass (CPB) may upregulate TF expression systemically, as well as at the site of surgical injury [62], which given the suggested TF-dependent mechanism of action of rFVIIa may lead to unwanted systemic thrombosis. We combined the reported thromboembolic adverse events from the 304 patients who received rFVIIa for refractory hemorrhage (see Table 3). There were 14 thromboembolic events, all within the adult subgroup, making the adverse event rate within that population 5.3%. The highest thromboembolic adverse event rate in those receiving rFVIIa was 25% [63]. However in this study, rFVIIa was administered alongside human factor VIII-von Willebrand factor concentrate, human fibrinogen, or both. All of these are pro-coagulants, and thus make it unclear as to how much these events are attributable to rFVIIa.

Prophylactic Use of Recombinant FVIIa
The only two randomized, controlled trials using rFVIIa in cardiac patients both evaluated its use as a prophylactic hemostatic agent (see Table 1). Diprose and colleagues [39] studied 20 adult patients undergoing complex noncoronary cardiac surgery. At cessation of CPB, they neutralized heparin and randomized patients to either rFVIIa 90 µg/kg or an equivalent dose of normal saline. Blood products and anti-fibrinolytics were then administered according to protocol. The treated group received a total of 13 units of allogeneic blood products compared with 105 units in the placebo group (relative risk of any transfusion, 0.26; p = 0.037). The groups did not differ for adverse events, both groups suffering one myocardial infarction and one stroke. Despite some self-reported limitations (underpowered and prone to type I error) they concluded that rFVIIa has exciting potential as a prophylactic hemostatic agent.

Ekert and colleagues [40] performed their trial in children under 1 year of age, undergoing surgery to correct congenital heart disease. They used a small dose (40 µg/kg) and a relatively standard hemostatic protocol. They evaluated bleeding after 20 minutes "based on previous experience," and if deemed excessive they gave a second equal dose of rFVIIa placebo. If bleeding persisted, then a third dose was given in the intensive care unit. The primary endpoint was time to chest closure; secondary endpoints were volumes of transfused blood products. They found prophylactic rFVIIa to significantly lengthen time to chest closure (p = 0.02) and have no impact on the secondary endpoints. There were no thromboembolic events in either group. The authors could find no clear explanation for their findings, but postulated higher doses may be required to achieve the correct bioavailability.


   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
References
 
Efficacy
The use of rFVIIa has been applied in two distinct ways: (1) prophylactically, with an aim of reducing postoperative bleeding, and (2) as a "rescue" therapy in hemorrhage refractory to other treatments. Its efficacy has been measured predominantly by studying subsequent blood loss as determined by chest tube drainage and transfusion requirements and it seems that rFVIIa is a potent hemostatic agent, particularly when used as a rescue therapy. However it has rarely been studied in isolation, patients having received significant volumes of blood products and anti-fibrinolytics prior to treatment. In the two reports in which it was used as the primary therapy in refractory hemorrhage, it significantly reduced hemorrhage. However, one of these was a case series of 2 patients [49], and the other a very small comparative study [14]. More evidence is required prior to confirming the role of rFVIIa in this scenario. Similarly, rFVIIa may have a prophylactic role, but currently there is not enough data to support its use in this manner.

Whether rFVIIa is more efficacious than other pro-coagulant interventions has not been established. There are few studies comparing the efficacy of rFVIIa; for example, comparing it with aprotinin or activated prothrombin complex concentrates. Authors, von Heymann and colleagues [41] studied rFVIIa in addition to fresh frozen plasma and platelet concentrates, but did not compare them directly; their data suggested rFVIIa had no incremental efficacy over these standard pro-coagulants.

The optimal dose of rFVIIa in cardiac surgery remains unclear. Studies in other specialities have demonstrated a significant reduction in blood loss with doses of 20 to 80 µg/kg when used prophylactically on healthy patients [8], but not in patients with pre-existing coagulopathy [64]. We have highlighted positive results with very low doses [43]. Thus, large randomized, controlled trials are required to establish the optimal dosing strategy for rFVIIa in cardiac surgery.

Safety
Establishing the safety of rFVIIa in cardiac surgical patients is difficult. Concerns exist in particular about exacerbation of conditions mediated by TF exposure to the circulation, such as disseminated intravascular coagulopathy, in which activated monocytes and platelets express TF. Thromboembolic complications in patients treated with rFVIIa as reported to the Food and Drug Administration database from 1999 to the end of 2004 were recently reviewed [6]. There was a suggestion of increased thromboembolic events in those treated for unlabeled conditions, but analysis of any relationship was hindered by various factors, including the inherent limitations of a passive surveillance system. However, these results are somewhat alarming, particularly as the morbidity and mortality from events such as stroke is so high.

In our review we aggregated the reported thromboembolic adverse event rate in patients treated for refractory hemorrhage. Our figure of 5.3% for adult patients is very similar to that quoted by Levy and colleagues [65] (6%) who recently reviewed the critical safety data from 13 Novo Nordisk-sponsored clinical trials of rFVIIa in patients with coagulopathy secondary to anti-coagulation, cirrhosis, or severe traumatic injury. They reported no significant difference between treated patients and placebo for the trial populations combined (p = 0.57). Similarly a recent randomized controlled trial of rFVIIa in trauma patients did not find an increased risk of thromboembolic events in the treatment group [66].

The key to assessing the risk-benefits of rFVIIa may be in the indication. One could argue that some patients have life threatening bleeding so severe as to warrant the consideration of any therapy to potentially prevent death, whereas the risks of using rFVIIa prophylactically are currently unjustifiable.

Cost
A single 90 µg/kg dose of rFVIIa to an 80 kg patient costs $4,500, and more than one dose may be required for maximal results. Although these costs may be offset against the costs of multiple transfusions, length of hospital stay, or even death, it is clear that rFVIIa is an expensive option, and one that currently many units may not be able to afford. Cost may be one factor restricting the number of large, multicenter trials, and cost-effectiveness analyses should be a part of any future trial involving rFVIIa.

Literature Recommendations
Recommendations regarding the use of rFVIIa in cardiac surgery have been previously made. Based on a literature review and an expert panel’s experience, Shander and colleagues [67] rated the use of rFVIIa in refractory hemorrhage in cardiac surgery as "appropriate," with the caveat that significant clotting factor replacement therapy had occurred. They suggested a dose of 41 to 90 µg/kg. Similar recommendations were made by Goodnough and colleagues [68], who suggested with some caution that a dose of 50 to 100 µg/kg be used in uncontrolled postoperative hemorrhage in the cardiac population. They added that a second dose could be considered if there was no response after 30 to 60 minutes. Roberts and colleagues [69] believed that the administration of rFVIIa was warranted in life-threatening hemorrhage, even in the absence of controlled clinical trials [69]. None of these authors recommend the prophylactic use of rFVIIa.

Our review concurs with these recommendations and has highlighted that rFVIIa seems to be effective at reducing refractory hemorrhage in a significant proportion of patients, both adult and pediatric. We believe that initial dosing levels should not rise above 90 µg/kg, as effectiveness has been demonstrated below this dose, and patients must have any consumed hemostatic factors replaced prior to considering rFVIIa. Although the findings of one small, randomized control trial into its prophylactic use have been encouraging, there is currently no evidence to support its use in this setting.

Limitations
Our recommendations regarding rFVIIa in refractory hemorrhage are based predominantly on small nonrandomized studies. Furthermore, in these cases the patients have often received multiple other blood products, which make it difficult to draw firm conclusions. However this systematic review and critique of the available literature is required to guide cardiac surgical practice, while larger randomized control trials are being performed.

Conclusion
In conclusion, recombinant factor VIIa is a potent pro-hemostatic agent. We suggest that there is a role for rFVIIa in the cessation of life-threatening refractory hemorrhage associated with cardiac surgery. There is currently little evidence to suggest a prophylactic role. Well-designed, multicenter, randomized controlled trials are required to definitively answer questions on the cost effectiveness, appropriate dosing regime, and safety profile of rFVIIa within specific patient groups.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 

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