Special Feature
Recombinant Factor VIIa in Hemorrhagic Shock and Massive Transfusion
By Grant E. O’Keefe, MD, Department of Surgery, Harborview Medical Center, University of Washington, Seattle, is Associate Editor for Critical Care Alert.
Dr. O’Keefe reports no financial relationship to this field of study.
Uncontrolled hemorrhage remains an important cause of death in the ICU. Patients with severe traumatic injuries, gastrointestinal hemorrhage, and ruptured abdominal aortic aneurisms are but a few examples of those who develop coagulopathy and hemorrhage that is not amenable to surgical control and may not respond to traditional approaches to blood product transfusion. Recent interest in the use of recombinant factor VIIa (rFVIIa: NovoSeven, Novo Nordisk, Denmark) in these circumstances has prompted a number of reports of this agent’s effectiveness in controlling bleeding that had not responded to other interventions. The majority of the data are related to the use of rFVIIa in the setting of bleeding and massive transfusion after traumatic injury, but there are some data regarding the use of the drug in hemorrhage from other causes. The purpose of this review is to summarize the existing data and to provide guidelines for the use of rFVIIa in critically ill bleeding patients who are receiving blood transfusions. At the time of writing, rFVIIa is not approved by the FDA for use in the management of patients with coagulopathy secondary to massive hemorrhage and transfusion and any use under such circumstances must be considered "off-label."
Coagulopathy Associated with Hemorrhagic Shock
Many factors contribute to the coagulopathy that often occurs following, though not directly due to, hemorrhagic shock. Through a variety of mechanisms, hypothermia, acidosis, clotting factor depletion and thrombocytopenia each affect hemostasis and contribute to "coagulopathic" bleeding. Hypothermia results in a general slowing of enzymatic processes, which, at temperatures below 35°C, markedly increases the time for in vitro clot formation.1 Similarly, acidosis (pH = 7.10) has been demonstrated to increase experimental hemorrhage and to reduce thrombin generation to the same extent as hypothermia (temperature = 32°C). Unlike hypothermia, however, acidosis appears also to reduce fibrinogen concentrations.2 As the final common pathway, the conversion of fibrinogen to fibrin is necessary for coagulation and effective hemostasis. Therefore, fibrinogen levels must be maintained at near-normal levels in order for any other haemostatic agents, including rFVIIa, to be effective.
Overview of the Mechanism of Action of RecombinantFactor VIIa
Blood coagulation is normally initiated when tissue factor (TF) is exposed and binds circulating factor VIIa, leading to the generation of a relatively small amount of thrombin which activates platelets, and factors V and VIII. This initial "TF-VIIa phase" subsequently leads to a second phase of clot propagation that results in rapid activation of greater quantities of prothrombin and factors VII, XI, X and XI.3 The exogenous administration of pharmacologic doses of rFVIIa results in markedly higher circulating concentrations and also appears to activate coagulation via generation of a TF-VIIa complex.4 Nevertheless, other observations suggest some of its activity may be independent of TF, through direct activation of factor X on the surface of activated platelets.5 Generally, however, rFVIIa is 100- to 1000-fold more effective in generating thrombin in the presence of TF than in its absence.3
Taken together, these data suggest that rFVIIa functions through both TF-dependent and TF-independent pathways, each of which leads to enhanced thrombin generation. Important effects of rFVIIa also include platelet activation, generation of tissue factor pathway inhibitor (as well as other feedback inhibitory loops), and thrombin-mediated increased production of fibrin.
Studies of rFVIIa in Critically Ill Patients with Coagulopathy and Massive Hemorrhage
rFVIIa was initially developed—and is approved—for use in hemophilia patients who have developed antibodies to factor VIII or factor IX. The drug is approved for this indication in the United States and other regions of the world (see www.novoseven-us.com. Site accessed October 13, 2005). In some countries, it is approved for the treatment of patients with acquired hemophilia and Glanzmann thrombasthenia who are not responsive to platelet transfusions.6 These indications however are uncommonly encountered relative to other causes of coagulopathy, such as those indicated below. More recently, it has been used to rapidly reverse the effects of oral anticoagulation, thrombocytopenia, platelet disorders, hepatic failure and in patients with uncontrolled bleeding due to haemostatic abnormalities arising in the setting of massive hemorrhage.7,8 The following section details the evidence regarding experience with rFVIIa specifically in the context of massive hemorrhage and associated transfusion. Notably, much of the evidence is observational, without the benefit of appropriate, untreated controls; a situation which must be addressed before the drug can be widely recommended. Finally, rFVIIa is costly. Its ultimate therapeutic role must take into consideration its cost particularly in the circumstances where alternative therapies exist.
A. Observational studies: Most data regarding the use of rFVIIa come from case reports, case series and relatively small cohort studies in which patients who received the drug were compared to those who did not. Initial case series have concluded that the use of rFVIIa as a "last resort" in patients with bleeding refractory to maximum standard therapy is effective and safe. An early review of the drug’s use in 40 patients with acute hemorrhage9 reported that in 32 (80%) patients the bleeding seemed to respond, at least partially, to the drug and in 18 of these the bleeding ceased. Of the 8 patients who did not respond, 6 had chronic liver disease. Patients received a median of 10 units packed red blood cells prior to rFVIIa and a median of 3 units afterwards. Similar reductions were seen in platelet and plasma transfusions after infusion of the drug. The recommended dose in hemophiliacs with inhibitors is 90 g/kg/dose. In this series, only 16 (40%) of patients received that amount in the initial infusion. The median number of doses per patient was two. There did not appear to be any dose-response, with cessation of bleeding occurring in patients receiving a wide range of rFVIIa. Overall, 23 (58%) patients died and this was attributed to uncontrolled bleeding in 7 patients.9 In this seriously ill group of patients, thromboembolic events occurred in 3 (8%) patients.
This early study is relevant for a number of reasons. First, it is difficult to sort out any relationship between dose and cessation of hemorrhage. This is not surprising, given the complex and often multifactorial nature of bleeding (coagulopathic with or without surgically correctable bleeding) in these patients. Nevertheless, there is no evidence that doses greater than 90 g/kg are beneficial, and the utility of multiple doses is unclear. Other studies have observed similar reductions in bleeding, but the effects on patient outcomes are less certain. In a study limited to 81 trauma patients who received the drug, the authors observed the prothrombin time to decrease in all patients tested before and after administration. Based upon clinical evidence of reversal of coagulopathic bleeding, 61 patients were considered to be "responders." Thirty-four patients (56%) survived and were discharged from hospital. The authors attempted to match patients who received rFVIIa to similar patients who did not. Although these data are somewhat difficult to decipher, it appears that rFVIIa was not associated with increased survival.10
Clark and colleagues reviewed 50 patients who received 10 units of packed red blood cells in a 24 hour period in order to determine the role of rFVIIa in the management of these critically ill patients. Most patients required massive transfusion in relation to surgery or gastrointestinal hemorrhage. A total of 17 (34%) patients died within 7 days. Not surprisingly, death was related to the severity of coagulopathy. Ten patients received rFVIIa. Most of these received a single dose of 90 g/kg. The patients given the drug had more severe coagulopathies than the 40 patients who did not. The case fatality rate in the patients receiving rFVIIa was 70%. The authors concluded that rFVIIa may not be beneficial in massively transfused patients, somewhat in contrast to other similar studies.11
B. Randomized trial: There is one recent randomized trial testing whether rFVIIa was an effective adjuvant therapy in trauma induced hemorrhage and coagulopathy. The investigators conducted a double-blind, placebo-controlled clinical trial in which both penetrating and blunt trauma patients were enrolled at 32 hospitals in 9 countries.6 The study is described and presented as 2 separate but parallel studies, for blunt and penetrating trauma patients, but are described as a single study here. Eligible patients were randomized if they received 6 units of packed red blood cells in a 4 hour period. Exclusion criteria eliminated patients with pre-hospital cardiac arrest, profound acidosis, severe traumatic brain injury and those who received 8 units of red blood cells prior to arrival at the hospital. Patients were randomly assigned to 3 doses of drug (200 g/kg, followed in 1 and 3 hours by 100 g/kg) or placebo intravenously. The primary endpoint used in the study was the number of red blood cell units transfused during the first 48 hours after the initial dose of drug (or placebo). Important clinical outcomes were mortality, days on the ventilator and days in the ICU. Subsequently, the authors defined an additional end point referred to as "massive transfusion" which was defined as the transfusion of > 20 units of red blood cells (12 units after the first dose of drug or placebo was given).
Overall, patients were quite seriously injured and the majority of both blunt and penetrating injury victims sustained trauma to 2 or more body regions (abdomen, extremity, thorax, etc). Mortality at 30 days was 25% overall. A reduction in units of red blood cells transfused was seen with rFVIIa, only in blunt trauma patients. The adjacent figure represents the number of patients in each group who were transfused > 20 units of red blood cells (massive transfusion). In both blunt and penetrating trauma patients the proportion of patients was reduced. This reduction was more marked and only statistically significant in blunt trauma patients. In summary, despite trends towards lower blood transfusion requirements and somewhat better clinical outcomes, the data are far from conclusive and do not support the wide use of rFVIIa under the conditions described by the authors of this study. As in the observational studies, the thromboembolic complication rate was quite low and not different between the treatment and placebo arms (see Figure).
Taken together, this study and the various observational studies suggest that rFVIIa reverses coagulopathy associated with hemorrhage and massive transfusion. Red blood cell transfusions may also be reduced, but clinical outcomes are not clearly improved. This is a common scenario when studying interventions in heterogeneous, critically ill patients, in whom it is often difficult to demonstrate important benefits of a particular treatment. Typically, studies with many more than a few hundred patients are required to test the interventions’ small-to-modest effects.
Assessing the Cost and Value of rFVIIa
The transfusion-related costs of patients with hemorrhage who require multiple blood products are significant and place unpredictable stress on transfusion services and blood banks. An agent such as rFVIIa could potentially reduce the burden placed by these seriously ill patients on blood banks. rFVIIa is itself costly, much more so than conventional hemostasis agents, and how this cost balances with the potential benefits of the drug is an important consideration. Loudon and Smith performed an interesting economic analysis to determine the conditions under which the use of rFVIIa might be cost-effective.12 Their analysis required the application of a number of assumptions, the most important of which is that after rFVIIa is given, no further blood transfusions are required. This is clearly not the case with most critically ill bleeding patients and certainly not supported by the literature. Nevertheless, their analysis is instructive. They determined that a single 100 g/kg dose, if no transfusions were required after it was given, would be cost effective only after patients had received 14 units of red blood cells. It is difficult to reconcile this study with the realities of clinical practice in which at best, bleeding is reduced, but rarely does it immediately cease. Clearly additional factors such as the impact of massive blood product utilization on blood reserves and the (albeit low) risk of transfusion reactions and disease transmission must be considered.
Summary
In general, existing data do not provide a strong framework on which to base the use of rFVIIa in bleeding patients with coagulopathy. Biochemical evidence of coagulopathy can be reversed, red blood cell transfusions can probably be reduced, but clinical outcomes are not clearly influenced. Given its high cost, institutions and intensivists must develop guidelines for the use of rFVIIa. Based upon existing data, these should be relatively restrictive and limit the drug to patients most likely to benefit. Identifying the appropriate patient is clearly a difficult task and generally will require clinician input for each situation. There is no evidence that the use of rFVIIa should be automatically triggered by any biochemical or transfusion threshold.
References
- Gubler KD, et al. The impact of hypothermia on dilutional coagulopathy. J Trauma. 1994;36:847-851.
- Martini WZ, et al. Independent contributions of hypothermia and acidosis to coagulopathy in swine. J Trauma. 2005;58:1002-1009.
- Butenas S, et al. Mechanism of factor VIIa-dependent coagulation in hemophilia blood. Blood. 2002;99:923-930.
- ten Cate H, et al. The activation of factor X and prothrombin by recombinant factor VIIa in vivo is mediated by tissue factor. J Clin Invest. 1993;92:1207-1212.
- Hoffman M, Monroe DM, III. The action of high-dose factor VIIa (FVIIa) in a cell-based model of hemostasis. Dis Mon. 2003;49:14-21.
- Boffard KD, et al. Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebo-controlled, double-blind clinical trials. J Trauma. 2005;59:8-15.
- Ghorashian S, Hunt BJ. "Off-license" use of recombinant activated factor VII. Blood Rev. 2004;18:245-259.
- Deveras RA, Kessler CM. Reversal of warfarin-induced excessive anticoagulation with recombinant human factor VIIa concentrate. Ann Intern Med. 2002;137:884-888.
- O’Connell NM, et al. Recombinant FVIIa in the management of uncontrolled hemorrhage. Transfusion. 2003;43:1711-1716.
- Dutton RP, et al. Factor VIIa for Correction of Traumatic Coagulopathy. J Trauma. 2004;57:709-718.
- Clark AD, et al. Last-ditch’ use of recombinant factor VIIa in patients with massive haemorrhage is ineffective. Vox Sang. 2004;86:120-124.
- Loudon B, Smith MP. Recombinant factor VIIa as an adjunctive therapy for patients requiring large volume transfusion: a pharmacoeconomic evaluation. Intern Med J. 2005;35:463-467.
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