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Ann Thorac Surg 2008;86:1038-1048. doi:10.1016/j.athoracsur.2008.05.013
© 2008 The Society of Thoracic Surgeons
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Review

Efficacy and Safety of Recombinant Activated Factor VII to Control Bleeding in Nonhemophiliac Patients: A Review of 17 Randomized Controlled Trials

Jean-François Hardy, MD, FRCPCa,*, Sylvain Bélisle, MD, FRCPCa, Philippe Van der Linden, MD, PhDb

a Department of Anesthesiology, University of Montreal, Université Libre de Bruxelles, Montreal, Quebec, Canada
b Department of Anesthesiology, CHU Brugmann, Université Libre de Bruxelles, Belgium, Germany

* Address correspondence to Dr Hardy, Département d'anesthésiologie, Centre Hospitalier de l'Université de Montréal, Hôpital Notre-Dame, Pavillon Lachapelle-Porte AS-1115-3, 1560 rue Sherbrooke est, Montréal, Québec, H2L 4M1, Canada (Email: jean-francois.hardy{at}umontreal.ca).


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Comment
 Acknowledgments
 References
 
We reassess all published randomized controlled trials that have evaluated the hemostatic efficacy or safety of recombinant activated factor VII (rFVIIa), or both, in nonhemophiliac patients. Seventeen trials published in 16 articles dealt either with the prophylactic (nine trials) or the therapeutic (eight trials) use of rFVIIa to prevent or to treat excessive bleeding. At present, the role of rFVIIa to prevent or to control bleeding and reduce transfusions in various patient populations remains unclear. In addition, the safety of rFVIIa remains a concern. Consequently, we conclude that the generalized use of rFVIIa to prevent or to control bleeding in nonhemophiliac patients can not be recommended.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Comment
 Acknowledgments
 References
 
Endogenous activated factor VII plays a crucial role in the coagulation process. Structurally, the clotting drug NovoSeven (Novo Nordisk A/S, Bagsvaerd, Denmark) is nearly identical to endogenous factor VIIa and is produced by recombination from a baby hamster kidney cell line. Supra-physiologic concentrations of activated factor VII are achieved by the administration of pharmacological doses of recombinant activated factor VII (rFVIIa). The activated FVII plays a central role in coagulation according to the newer, cell-based concepts of coagulation that have recently emerged [1]. To generate thrombin, the activated FVII needs either tissue factor (TF) or activated platelets (TF-independent generation).

During initiation of coagulation, TF exposed on the subendothelium forms a complex with circulating factor VIIa. The TF-FVIIa complex activates factor X and leads to the generation of a small quantity of thrombin. This small quantity of thrombin activates platelets and co-factors, "priming" the system for the subsequent generation of large amounts of thrombin. Factor IX, also activated during the initiation phase, acts as a procoagulant signal, and initiates (on the surface of platelets) the cascade leading to the "thrombin burst" (ie, the generation of sufficient thrombin to cleave enough fibrinogen to result in a strong clot). Ultimately, the process is completed when fibrin is cross-linked to enhance durability, and when platelets retract, stabilizing the platelet plug.

At least two mechanisms, either TF-dependent or independent, may explain the hemostatic effect of rFVIIa administered to (previously normal) patients with uncontrolled hemorrhage [2]. If TF is available to complex rFVIIa, it seems likely that thrombin generation will be mediated by a TF-dependent pathway, given the marked affinity of factor VIIa for TF. If TF is separated from the bloodstream by the growing hemostatic plug, rFVIIa may enhance coagulation by directly stimulating factor X on the surface of platelets, resulting in the "thrombin burst" necessary for the formation of a stable clot. It is most likely that both mechanisms are involved. Theoretically, the TF-dependent activation remains localized and the TF-independent activation of factor X is not supported by endothelial cells, preventing the systemic initiation of coagulation.

At present, rFVIIa is approved for the prevention and the treatment of bleeding in patients with hemophilia who present antibodies to factors VIII or IX. Numerous case reports and case series have been published describing its successful use in patients with no prior defect of hemostasis to control bleeding secondary to trauma or major surgery. For the last 5 years the estimated number of patients treated with rFVIIa has grown rapidly, mainly for off-license indications.

Prior to its introduction in general clinical use, a new treatment has to be proven both effective and safe. The gold standard in establishing the benefits and harms of a novel therapeutic intervention is the randomized controlled trial (RCT). In this review, we reassess all published RCTs that have evaluated the hemostatic efficacy or safety or both of rFVIIa in nonhemophiliac patients. In total, at the time of this writing, 17 placebo-controlled, double-blind RCTs have been published in 16 articles on the use of rFVIIa to control bleeding in nonhemophiliac patients. Recombinant FVIIa was administered either prophylactically to prevent excessive bleeding in nine RCTs (938 randomized patients) [3–11] or therapeutically to treat excessive bleeding in eight RCTs (1171 randomized patients) [12–18].


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Comment
 Acknowledgments
 References
 
We searched MEDLINE for randomized controlled trials published either in English or French on the use of rFVIIa (activated recombinant factor VII/NovoSeven [Novo Nordisk A/S]) outside hemophilia. To be included in this review, studies had to be prospective, randomized, blinded, and placebo-controlled and evaluated for the efficacy and safety of rFVIIa in nonhemophiliac patients. Retrospective, nonrandomized, open label, nonplacebo controlled studies were excluded, as were those conducted in patients with hemophilia. Case series, retrospective reviews and registers were considered only for the "Comment" section of the text.

Seventeen trials published in 16 articles were identified. Trials dealt either with the prophylactic or the therapeutic use of rFVIIa to prevent or treat excessive bleeding in a variety of clinical contexts. Main data were summarized in tabular format and are presented in Tables 1 and 2. Go


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  		Table 1 Main Characteristics and Key Results of Trials Evaluating the Prophylactic Use of rFVIIa Outside Hemophilia
 

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  		Table 2 Main Characteristics and Key Results of Trials Evaluating the Therapeutic Use of rFVIIa Outside Hemophilia
 

   Results
Top
 Abstract
 Introduction
 Methods
 Results
Comment
 Acknowledgments
 References
 
Efficacy of rFVIIa for the Prevention of Excessive Bleeding and the Reduction of Transfusions
Table 1 summarizes the main characteristics and key findings of the nine trials that have evaluated the prophylactic use of rFVIIa outside hemophilia. In more than half of the trials, rFVIIa was not efficacious [4, 5, 7, 8, 10].

The trial by Lodge and colleagues [6] on the use of rFVIIa to reduce bleeding and transfusions in liver transplantation found a statistically significant but small difference in the proportion of transfused patients. At best, the percentage of patients avoiding transfusions altogether was 10% (6 of 62 in the 60 µg/kg group; Table 1). The use of red blood cells (RBCs), fresh frozen plasma, and platelet concentrates was similar in all groups, and there were no other clinically important differences between the groups.

The authors of a pilot study on the use of rFVIIa to reduce allogeneic transfusions in patients undergoing complex noncoronary cardiac surgery with cardiopulmonary bypass stated that "rFVIIa significantly reduces the need for allogeneic transfusion" [9]. However, 1 patient in the rFVIIa group was excluded from the "per protocol analysis" after unblinding of treatment allocation because of the sudden onset of mediastinal hemorrhage 2 hours after surgery while the patient was in the intensive care unit. The patient consumed 72 units of allogeneic blood products, two further doses of rFVIIa, and returned to the operating room on two occasions before a posterior aortic tear was discovered. When the results were analyzed by intention-to-treat (also presented in the article), the results of the pilot study were negative [9].

The latest trial on the prophylactic use of rFVIIa evaluated the efficacy of the drug to reduce transfusions in burn patients undergoing excision and skin grafting. Interpretation of the results is difficult, as they are presented as "total blood products transfused/full thickness burn wound excised and grafted (% total body surface area)" [11]. We were unable to determine how this applies clinically to a given burn patient coming to the operating room for excision and skin grafting and at which percent (%) of total body surface area the use of rFVIIa becomes beneficial. The effect of treatment on intraoperative bleeding is not reported, and all the other outcomes of interest were similar in both groups (Table 1).

The study by Friederich and colleagues [3] showed that rFVIIa reduced perioperative blood loss and eliminated the need for transfusion in patients undergoing retropubic prostatectomy. Nevertheless, most clinicians would consider that blood losses in the placebo group were much greater (median, 2,688 mL) than those encountered in contemporary clinical practice [19], especially in light of the recent advancements in minimally invasive surgical techniques [20, 21]. Accordingly, the usefulness of rFVIIa to reduce bleeding and transfusions in patients undergoing retropubic prostatectomy, as described in 2003, probably would not apply today.

In summary, the role of rFVIIa to prevent excessive bleeding and reduce transfusions in a variety of patients at risk of hemorrhage during surgery remains uncertain.

Efficacy of rFVIIa for the Treatment of Excessive Bleeding and the Reduction of Transfusions
Table 2 summarizes the main characteristics and the key findings of the eight trials (published in seven articles: two studies [13] were published simultaneously) that have evaluated the therapeutic use of rFVIIa outside hemophilia. Three studies evaluated surgical indications, whereas five explored medical indications.

Recombinant FVIIa was used as adjunctive therapy for the control of bleeding in severely injured trauma patients in two randomized, placebo-controlled, double-blind clinical trials (one in blunt trauma and one in penetrating trauma). The primary endpoint of the study "was the number of RBC units (autologous RBCs, allogeneic RBCs, and whole blood) transfused during the 48-hour period after the first dose of trial product." Whether in blunt or penetrating trauma, use of RBC, fresh frozen plasma, and platelet concentrates was similar in placebo and treatment groups when all patients are considered (intention-to-treat analysis) (Table 2). There was a significant reduction of transfusions in the blunt trauma patients treated with rFVIIa who were alive at 48 hours (post hoc analysis).

The other surgical trial evaluated the effect of rFVIIa in spinal surgery patients who reached a bleeding trigger (10% blood loss; expected total losses ≥ 20% total blood volume) during the operation [18]. Mean blood losses and transfusion volume were not different between groups. When adjusted for duration of surgery, number of vertebral segments fused and estimated blood volume, blood loss, and transfusion volume were reduced significantly in treated patients.

However, as presented, the results do not allow us to determine in which patients, based on estimated blood volume, planned duration of surgery, and number of vertebral segments fused, the use of rFVIIa may be beneficial.

Positive findings on the therapeutic use of rFVIIa were observed in patients with intracerebral hemorrhage (ICH) [15]. Mayer and colleagues [15] showed that the administration of rFVIIa within 4 hours after the onset of symptoms of ICH is associated with a reduced growth of the hematoma and a decrease in 90-day mortality. In addition, an improvement in functional outcomes at 90 days was observed in the treatment groups, as assessed by four neurologic outcome scales (Modified Rankin Scale, Barthel Index, Extended Glasgow Outcome Scale, and National Institutes of Health Stroke Scale), despite an increase in the frequency of thromboembolic events (see as follows). These positive results were not confirmed by a subsequent large multicenter, phase III trial involving 841 patients of which 821 were randomized. The results of this latter study (published after the acceptance of our review article and thus not included in Table 2) concluded that "Hemostatic therapy with rFVIIa reduced growth of the hematoma but did not improve survival or functional outcome after intracerebral hemorrhage [22].

Three other studies report the use of rFVIIa to treat excessive bleeding in a medical context. The first was in cirrhotic patients presenting with upper gastrointestinal bleeding [12], the second in children with Dengue fever [16], and the third in adults after hematopoietic stem cell transplantation [17]. In all cases, bleeding control and transfusion requirements were similar in both groups.

In summary, the role of rFVIIa to treat excessive bleeding (or critical bleeding, as in the case of ICH) and reduce transfusions in a variety of medical and surgical conditions remains unclear.

Safety of rFVIIa When Used for the Prevention or Treatment of Excessive Bleeding and the Reduction of Transfusions
The incidence of adverse events (including thromboembolic events) was not increased in the nine trials evaluating the prophylactic use of rFVIIa (Table 1). With one exception, the incidence of adverse events was also not increased in the trials evaluating the therapeutic use of rFVIIa (Table 2).

An increase in the incidence of arterial thrombotic events was observed in the ICH trial published by Mayer and colleagues in 2005 [15]. Total (venous and arterial) serious adverse thromboembolic events occurred in 2% of patients receiving placebo and in 7% of all patients treated with rFVIIa (p = 0.12). The incidence of venous thromboembolic events was the same (2%) in both groups. However, the incidence of arterial serious adverse thromboembolic events (ie, myocardial ischemic events and cerebral infarctions) was increased in rFVIIa patients (0% vs 5%; p = 0.01). The incidence of fatal or disabling thromboembolic events judged to be related to treatment was the same (2%) in both groups. The incidence of arterial thromboembolic events was also increased in Mayer and colleagues' latest ICH trial. Arterial events were more frequent in the group receiving 80 µg/kg of rFVIIa than in the placebo group (9% vs. 4%, P = 0.04). Pooled data from three ICH trials supported the increased risk of arterial thromboembolic events with rFVIIa, particularly at higher doses (ie, 120 to 160 µg/kg) [23].

The majority of studies excluded patients at risk of thrombosis, such as those with known hypercoagulopathy, history of pulmonary embolism, or deep vein thrombosis, stable or unstable angina pectoris, myocardial infarction, intermittent claudication, transient ischemic attack or ischemic stroke, signs of cardiac ischemia, and so forth. In one case, midway through the trial, a change was made "to exclude patients with any history of thrombotic vaso-occlusive disease" [15]. Such strict exclusion criteria may have contributed to the 12% enrollment rate of screened patients mentioned in that trial [15] and raises the possibility that the incidence of adverse thrombotic events might be higher in a broader ICH patient population [24].

In summary, the observations made in 16 of 17 published RCTs on the use of rFVIIa to prevent or to treat excessive bleeding in nonhemophilia patients do not report an excess of serious (particularly thrombotic) adverse events. The use of rFVIIa in highly selected ICH patients with minimal (but critical) bleeding was associated with an increased risk of arterial thrombosis.


   Comment
Top
 Abstract
 Introduction
 Methods
 Results
 Comment
Acknowledgments
 References
 
Our review of all published RCTs leads us to conclude that the role of rFVIIa to prevent excessive bleeding and reduce transfusions in a variety of patients at risk of hemorrhage during surgery remains uncertain. The role of rFVIIa to treat excessive (or critical, in the case of ICH) bleeding and to reduce transfusions in a variety of medical and surgical conditions is also uncertain. The most impressive benefits of the therapeutic use of rFVIIa were found in patients with ICH, but these results were not confirmed in a recent phase III trial. Thus, at present, the generalized administration of rFVIIa to nonhemophiliac patients at risk of excessive (or critical) bleeding can not be recommended.

Our results concur with those of the meta-analysis published by Stanworth and colleagues [25] that included 13 trials. Six trials examined the prophylactic use of rFVIIa and seven examined the therapeutic use of the drug. The authors conclude that the effectiveness of rFVIIa as a more general hemostatic drug, either prophylactically or therapeutically, remains uncertain compared with its role in the management of patients with hemophilia, and that its use should be restricted to clinical trials. The results of three additional studies on prophylaxis [5, 10, 11] and of two studies on treatment [18, 22] with rFVIIa are in line with the conclusions of Stanworth and colleagues' [25] meta-analysis.

Recently, another meta-analysis evaluated the efficacy and safety of rFVIIa in major surgical procedures [26]. The systematic review included seven trials [3–9], whereas the efficacy analysis was conducted in five trials [3, 4, 6, 8, 9]. The review concluded that patients receiving rFVIIa had a reduced risk of allogeneic red cell transfusion but the authors were unable to comment on transfusion needs or perioperative bleeding. The selection of studies and the very positive results of the 40 µg/kg group in the Friederich and colleagues' [3] trial may help explain the discrepancy between meta-analyses.

Numerous case reports, case series, and registers have suggested that rFVIIa may be efficacious for the prophylaxis or for the treatment of severe bleeding in different clinical contexts [27–35]. Observational studies report success rates that vary from 69% [32] to 80% [31, 34]. It is rather interesting to note that these rates are similar to those reported in trials evaluating the therapeutic potential of rFVIIa. When aggregating the data on the control of bleeding in the three randomized controlled trials that reported this variable [12, 16, 17], the number of patients with reduced bleeding was 158 in 210 (75.2%) in the rFVIIa group versus 130 in 172 (75.6%) in the control group [25]. Thus, whatever the circumstances, approximately 75% of patients seemed to respond to treatment, whether it be rFVIIa or placebo.

Notwithstanding the interest of case reports, case series, and registers, the gold standard in establishing the benefits and harms of a technology is the RCT [36]. The RCT is a study in which subjects are randomized to an intervention or control and followed systematically for occurrence of outcome. Randomization and blinding of intervention avoid observator bias, which would otherwise be inevitable. Thus, as opposed to observational, single-arm interventional studies or those using historical controls, the RCT is the only study design where causality (both for benefits and for harms) can be established. Unfortunately, and contrary to the hopes raised by case reports, case series and registers, results of published RCTs have failed to demonstrate convincingly the efficacy of rFVIIa outside hemophilia.

Why have such disappointing results been observed? Possible explanations are numerous and include inadequate doses of the drug or inappropriate timing of administration, a suboptimal clotting environment at the time of drug administration, and adherence to a transfusion protocol for red cells and hemostatic blood components. In studies evaluating the prophylactic use of rFVIIa, doses varied between 20 and 120 µg/kg and were either not repeated or at intervals of 2 or 5 hours (Table 1). Surprisingly, the study reporting unquestionable efficacy of rFVIIa used the smallest doses administered only once in the early operative phase [3]. Despite the use of more generally accepted dosages (of the order of 90 µg/kg) repeated at a time interval in relation with the half-life of 2 to 3 hours of rFVIIa [37, 38], all the other trials generated results that were either negative [4, 5, 7, 8, 10] or clinically difficult to interpret [6, 9, 11]. In studies evaluating the therapeutic use of rFVIIa, in general, doses were higher and were repeated more frequently. This is congruent with the known pharmacokinetic profile of rFVIIa, whereby clearance is increased and half-life is shortened in the presence of bleeding [37, 39, 40]. Although doses higher than 50 µg/kg seem to be more efficacious [26], the level of FVII required to achieve hemostasis in different clinical circumstances remains uncertain [38, 41].

Coagulopathy associated with massive transfusion remains an important clinical problem. It is an intricate, multifactorial, and multi-cellular event [42]. Coagulopathy will result from hemodilution, hypothermia, use of fractionated blood products, disseminated intravascular coagulation (DIC), and shock, which may be the primary initiator of the process in the case of trauma [43]. In elective surgery patients, a decrease in fibrinogen concentration is observed initially while thrombocytopenia is a late occurrence [44, 45]. Disseminated intravascular coagulation often complicates the management of massive transfusion and is secondary to the systemic and excessive activation of coagulation. It may be defined by the association of hemostatic defects related to the excessive generation of thrombin and fibrin (with or without clinical signs) and the excessive consumption of platelets and coagulation factors [42]. To varying degrees, disseminated intravascular coagulation occurs in cardiac operations using cardiopulmonary bypass [46].

Post-injury coagulopathy depends on (1) the severity of tissue injury (injury severity score > 25), (2) magnitude of shock (systolic blood pressure < 70 mm Hg and pH < 7.10), and (3) inability to maintain a core temperature > 34°C [47]. In approximately 25% of trauma patients, a clinically significant coagulopathy is present on arrival in the emergency room [48]. This acute coagulopathy seems to be secondary to activation of the anticoagulant pathway (activation of protein C by the thrombin–thrombomodulin complex) and fibrinolytic pathway (release of tissue plasminogen activator and reduction of plasminogen activator inhibitor-1) [49]. Treatment strategies include the maintenance of adequate tissue perfusion, the correction of hypothermia and anemia, and the use of hemostatic blood products to correct microvascular bleeding. Several treatment algorithms based on near-patient coagulation monitoring have been proposed [50–52]. Correction of shock and acidosis, rewarming, and rapidly ensuring adequate levels of fibrinogen and platelets will promote hemostasis [53–55] and should assist the effect of rFVIIa [56, 57]. Conversely, it has been shown in animal experiments that the effects of rFVIIa were most impressive in hypothermic animals, suggesting that rFVIIa remains efficacious in the presence of hypothermia [58–60].

Hypothetically, and counter-intuitively, the administration of rFVIIa may not be the optimal line of treatment in patients with coagulopathy. Effective management of ongoing disseminated intravascular coagulation requires the simultaneous suppression of thrombin generation and fibrinolysis [46]. The administration of rFVIIa will enhance thrombin generation and could therefore, theoretically at least, contribute to the ongoing disseminated intravascular coagulation. Increased thrombin generation will also stimulate endothelial cell release of tissue plasminogen activator and may contribute to ongoing fibrinolysis [61, 62]. Finally, increased thrombin generation will lead to increased activation of protein C and anti-coagulation [49].

An important consideration when treating hemorrhage pertains to the maintenance of an optimal hemostatic environment. Hematocrits (as high as 35%) may be required to sustain hemostasis in bleeding patients undergoing massive transfusion [42]. Erythrocytes modulate the biochemical and functional responsiveness of activated platelets, suggesting that erythrocytes contribute to thrombosis and hemostasis, and supporting the concept that thrombus formation is a multi-cellular event [63–65]. Another mechanism by which erythrocytes modulate hemostasis is the rheological effect of red cells on the margination of platelets [66], enhancing the near-wall concentration of platelets up to approximately 7 times the average concentration [67]. Maintaining adequate levels of circulating platelets is important given (1) our current knowledge of hemostasis in which platelets play a pivotal role [41], and (2) the findings from studies [47, 68–70] showing that survival is improved in massively transfused patients who received increased numbers of platelet concentrates.

We used the intent-to-treat principle to evaluate the results of RCTs [36]. Inclusion of only those subjects who followed the protocol as planned (per protocol analysis) introduces a number of biases. Subjects who are lost to follow-up or who refuse treatment (despite initial consent) are likely to be different in important ways from other subjects. The intent-to-treat principle takes into account the inherent difficulties of a treatment. Excluding patients in whom treatment was difficult or impossible will bias the overall results on the efficacy of an intervention. Finally, some important outcomes can not be predicted at the time of randomization, for if they had been predicted, the patient would not have been included in the study. For example, it is impossible to determine ahead of time which patient(s) will present with overt surgical bleeding after a cardiac operation [9], or those who will be alive at 48 hours after trauma [13]. Thus, the results of the analysis by intent-to-treat truly reflect the efficacy of an intervention in the conditions of the study.

Prevention of excessive bleeding and transfusions can be achieved by different pharmacological and nonpharmacological interventions. Obviously, to be adopted in clinical practice, an intervention must be efficacious, but safety remains a major concern. When administered at pharmacological doses, blood levels of activated factor VII are 1,000 times greater than normal. As previously mentioned, rFVIIa augments thrombin generation by TF-dependent and independent pathways, enhances the adhesion, deposition and activation of platelets (thrombin dependent), and inhibits fibrinolysis [41, 71–73]. By definition, any therapy that promotes hemostasis is likely to induce thrombosis. Thus, a favorable balance between hemostasis (the desired effect) and thrombosis (an unwanted, potentially serious adverse event) may be difficult to achieve. In theory, because they are mediated by TF, the effects of rFVIIa should remain localized [74]. Nevertheless, Stanworth and colleagues' [25] observed a trend toward an increase in thromboembolic events associated with the use of rFVIIa either prophylactically (pooled RR, 1.25; 95% confidence interval, 0.76 to 2.07) or therapeutically (pooled relative risk, 1.50; 95% confidence interval, 0.86 to 2.62) [25].

Tissue factor may be expressed at sites other than the site of hemorrhage, resulting in undesirable thrombotic events [75]. In animals with no hemostatic defect and a carotid artery lesion, rFVIIa increases the incidence of thrombosis [58, 76]. This may help explain the increased incidence of arterial serious adverse thromboembolic events observed in ICH patients [15]. The "potential increased risk of arterial thromboembolic adverse events with use of NovoSeven, including myocardial ischemia, myocardial infarction, cerebral ischemia and/or infarction" (http://www.fda.gov/medwatch/safety/2005/safety05.htm#NovoSeven) that occurred despite very strict exclusion criteria, as mentioned earlier, raises the possibility that the incidence of adverse thrombotic events might be higher in a broader ICH patient population [24].

A review of the Adverse Event Reporting System of the United States Food and Drug Administration documented a total of 431 adverse event reports for rFVIIa between 1999 and 2004 [77]. Of these, 168 reports described 185 thromboembolic events, the majority of which (151/185) were for unlabeled indications. Reported adverse events included cerebrovascular accident (n = 39), acute myocardial infarction (n = 34), other arterial thromboses (n = 26), pulmonary embolism (n = 32), other venous thromboses (n = 42), and clotted devices (n = 10). In 72% of the 50 reported deaths, the probable cause of death was the thromboembolic event. A major concern was that the use of rFVIIa and spontaneous reporting of adverse events increased steadily during the study period, while reporting of adverse events originating from controlled trials decreased. The authors concluded that RCTs are needed to establish the safety and efficacy of rFVIIa in patients without hemophilia, and we believe this conclusion still applies.

Conclusions
The lack of adequately powered, randomized studies limits the capacity to draw firm conclusions on the optimal role of rFVIIa in our therapeutic armamentarium, whether for the prevention or for the treatment of coagulopathy. Consequently, and while awaiting a clearer demonstration of its benefits, confirmation of its safety, determination of the optimal dosage, and appropriate timing of administration, the generalized use of rFVIIa to prevent or to control bleeding in nonhemophiliac patients can not be recommended.

Recombinant FVIIa may be considered with caution in patients with refractory life-threatening hemorrhage when all conventional measures (including embolization, surgery, rewarming the patient, and so forth) have failed [78]. It should be considered as an adjunct to such measures, rather than in replacement of such measures. Inasmuch as possible, an optimal hemostatic environment must be ensured. Thus, rFVIIa should be considered relatively late in the management of excessive bleeding. Introduction of rFVIIa at a very early stage of hemorrhage will expose an unnecessarily large number of patients to an extraordinarily expensive therapy whose efficacy remains unclear. On the other hand, criteria such as the Sequential Organ Failure Assessment and response to the initial dose of rFVIIa may help determine when treatment is futile [79].

Finally, all patients exposed to rFVIIa should be included in ongoing registers. Although registers can not demonstrate the efficacy or the safety of a drug, they may be helpful to identify specific clinical circumstances in which rFVIIa could be useful, and in this way, they may assist in planning future RCTs on the benefits and risks of rFVIIa used to control bleeding in nonhemophiliac patients.


   Acknowledgments
Top
 Abstract
 Introduction
 Methods
 Results
 Comment
 Acknowledgments
References
 
The authors would like to thank Professor Brigitte Jude of the Université de Lille, Lille, France for her constructive review of the manuscript.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Comment
 Acknowledgments
 References
 

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