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Ann Thorac Surg 2005;80:3-5
© 2005 The Society of Thoracic Surgeons
a Department of Anesthesiology, St. Louis, Missouri, USA
b Department of Pathology and Immunology, St. Louis, Missouri, USA
c Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
* Address reprint requests to Dr Despotis, Department of Anesthesiology, Box 8054, Washington University School of Medicine, 660 S Euclid Ave, St. Louis, MO63110 (Email: despotig{at}notes.wustl.edu).
Recombinant activated factor VIIa (rFVIIa) is currently FDA approved for the management of bleeding related to hemophilia in patients with factor inhibitors. Although the off-label use of this agent has been reported to be successful in reversing life-threatening bleeding in a number of clinical scenarios [1], the body of literature for off-label use predominately consists of case reports and anecdotal experience with limited data from randomized clinical trials.
The mechanism of action of activated factor VII involves generation of thrombin by initial binding to tissue factor and subsequent activation of factor X on the platelet surface; activated factor X in combination with factor V (ie, prothrombinase complex) leads to localized thrombin formation. This occurs in the absence of factor VIII or factor IX. The extent of thrombin activation relates to the concentration of activated factor VII achieved. Partial thrombin activation occurs at rFVIIa concentrations approximating 50 nM, whereas full activation of thrombin, referred to as a "thrombin burst," is achieved with higher levels (100 to 150 nM) [1]. This pronounced thrombin activity on thrombin-activated platelet surfaces leads to a stabilized thrombin plug and tight fibrin structure resistant to lysis. One of the reasons postulated for the potential safety of rFVIIa is that it should be effective predominately at the sites of vessel injury where there is localized expression of tissue factor by subendothelial cells. However, the risks of thrombosis associated with rFVIIa may be theoretically increased when there is systemic (eg, disseminated intravascular coagulation) or localized, pathologic expression of tissue factor (eg, atherosclerotic coronary artery disease).
Because recombinant FVIIa usage has been steadily increasing in non-approved settings, significant concerns have arisen about its safety, efficacy, and costs. Dosing of rFVIIa for non-approved settings is not standardized and is evolving in part based on cost considerations and also evidence that doses lower than the label-recommended dose (ie, 10 to 20 mcg/kg) for hemophilia patients with inhibitors may be effective for off-label settings [2]. Currently the decision whether to use rFVIIa for patients with uncontrolled bleeding continues to be one that must be made by individual physicians, assisted by their hospital pharmacotherapeutics and transfusion committees [2].
Early administration of rFVIIa should be considered in patients with intracranial hemorrhage based on reduced mortality (ie, 38% reduction) observed in patients who received this agent in a recent study [3]. Use of rFVIIa as a rescue therapy should also be considered in patients with life-threatening bleeding that is unresponsive to routine hemostatic therapy (eg, trauma, perioperative bleeding). Off-label administration of rFVIIa may also benefit patients who have a relative contraindication to blood or blood component transfusions, such as patients with multiple red cell allo-antibodies, patients who display refractoriness to platelets, and patients with IgA deficiency for whom plasma is unsafe, as well as patients who refuse transfusion (eg, patients who are Jehovah’s witnesses). However, more studies are warranted to assess the benefits as well as the safety of rFVIIa before its widespread use can be recommended as either first line therapy or as a prophylactic measure based on lack of safety data in other settings.
Thrombotic risk profile has to be considered as one of the most important issues that is still unresolved based on the infrequent reports of life-threatening thrombotic complications that have been described with use of this agent [1, 4, 5]. Of more than 170,000 standard doses of rFVIIa given after its approval, almost all to patients with hemophilia and factor VIII inhibitors, fewer than 1:11,300 thrombotic events have been reported [1]. In this review, five thromboembolic events were reported, whereas acute myocardial infarctions were reported in 6 patients and cerebrovascular disorders were reported in 4.
Use of rFVIIa has also been described for the management of intractable bleeding after cardiac surgery in several case reports and a case series [6]. More recently, Halkos and colleagues [7] described a series of 9 patients whose intractable bleeding after cardiac surgery improved after administration of rFVIIa without any obvious complications, thrombotic or otherwise [7]. Similarly, Karkouti and colleagues [8] observed a substantial beneficial effect of rFVIIa with respect to reduced bleeding and transfusion in a series of 51 patients who received rFVIIa for life-threatening, unresponsive bleeding when compared with a matched control group. However, they also observed an increase incidence of renal failure, a trend toward a higher stroke rate as well as multiorgan system failure in 2 patients who received rFVIIa [8].
The publication by Raivio and colleagues [9] in the current issue of this journal adds to the cardiac surgical database regarding the off-label use of rFVIIa in the management of life-threatening bleeding. Although Raivio and colleagues [9] demonstrate support for previous observations that this agent can be effective in the management of excessive, life-threatening bleeding (13 of 16 or 81% response rate), these authors also highlight that there may be some potential risk as indicated by the cited incidence (ie, 25%) of thrombotic complications observed in this series. Raivio and colleagues [9] include only overt episodes of thrombosis as thromboembolic complications (4 of 16 patients), but if one speculates that an additional 3 patients (ie, an additional 19%) may have displayed evidence of intravascular thrombosis based on the pathophysiology of multiorgan system failure, which has been postulated to occur at a higher frequency in patients who receive rFVIIa, then the thrombosis incidence increases to a worrisome 44%. This is consistent with the recent findings of Mayer and colleagues [3] who demonstrated that the use of rFVIIa was associated with a 350% increase in the incidence of thrombotic complications. However, the absolute risk of thromboembolic events in the rFVIIa-treated group in the study of intracranial bleeding was 7%, much less than the 25% (or as much as 44%) seen in the current study in cardiac surgery patients, which suggests that cardiac surgery patients may be at increased risk of thromboembolic events with rFVIIa administration compared with other patient groups.
Although there have only been rare, isolated reports of either extracorporeal circuit [10, 11], ventricular assist devices [12, 13], or extracorporeal membrane oxygenation [5], intracardiac [14–17] or pulmonary artery catheter thrombosis, the incidence of these complications cannot be determined based on underreporting of these events. In addition, the incidence of thrombotic complications may be substantially higher if the subset of patients who have neurologic or myocardial injury as well as multiorgan system failure secondary to thrombosis are included. A greater percentage of cardiac surgical patients may be at risk for thrombotic complications related to frequently undiagnosed, pre-existing hereditary or acquired thrombophilic states, or both, as well as several factors specific to this clinical arena. Cardiac surgical patients who have a history of thrombosis or thrombotic complications, established thrombotic disorders (eg, factor V Leiden, congenital or acquired ATIII deficiency, anti-phospholipid syndrome, and so forth), or systemic or localized advanced atherosclerosis (eg, coronary artery disease with cerebrovascular disease, stroke or peripheral vascular disease) may be at increased risk based on the increased potential for development of localized or systemic intravascular thrombosis as associated with these conditions.
Systemic activation of the hemostatic system due to stimulation of both the contact and, more importantly, tissue factor pathways occurs almost invariably with extracorporeal circulation despite use of high-dose heparin anticoagulation. Several studies have demonstrated that physiologic anticoagulants like antithrombin III, protein C, and protein S are at levels approximately 50% of normal after cardiac surgery, equivalent to heterozygotic congenital deficiency of these anticoagulant proteins. A substantial percentage (ie, 25% to 40%) of patients who develop heparin associated anti-platelet antibodies after cardiac surgery may also be at increased risk. Cardiac surgical patients with congestive heart failure or acute hypoperfusion may also be at increased risk for thrombotic complications based on an upregulated hemostatic system.
Use of pharmacologic interventions to preserve the hemostatic system during extracorporeal circulation in an attempt to reduce bleeding and transfusion may also predispose susceptible patients to thrombotic complications. Use of agents that only inhibit fibrinolysis (ie, antifibrinolytic agents or half dose aprotinin in patients weighing more than 70 kg) and lead to fibrin accumulation in a subset of patients, or that inhibit protein C (ie, when aprotinin levels exceed 250–300 KIU/mL) may also change the risk profile for thrombotic complications in susceptible patients (ie, patients with factor V Leiden mutation). However, the latter of these two (ie, inhibition of protein C by aprotinin) may be potentially avoided if the dosing regimen for aprotinin is adjusted by factoring in weight and renal function. Empiric administration of 1-deamino-8D-arginine vasopressin or platelets may also predispose susceptible patients to develop thrombotic complications.
Excessive thrombin generation and activity may be secondary to inadequate anticoagulation during extracorporeal circulation due to either antithrombin deficiency or lower levels of unfractionated heparin. Sustained activation of the hemostatic system in patients with disseminated intravascular coagulation or patients who require extracorporeal membrane oxygenation or ventricular assist devices may also increase the risk for development of thrombotic complications. Accordingly, we previously reported a patient who had a fatal thrombosis after administration of activated prothrombin complex concentrate, who had also received two doses of rFVIIa more than 6 hours earlier while being supported by extracorporeal membrane oxygenation [5]. Because of this experience, our institutional policies recommend that patients should not receive combination therapy with both activated prothrombin complex concentrate and rFVIIa, and clinicians should confirm the adequacy of anticoagulation for patients on extracorporeal membrane oxygenation or ventricular assist devices [2]. Any clinical scenario that involves activation of the hemostatic system by systemic circulation of tissue factor (ie, disseminated intravascular coagulation) will potentially convert the localized mechanism of action of rFVIIa to a generalized one and potentially lead to thrombosis. Accordingly, our previously published policies suggested that until adequate safety data is available for the off-label use of factor concentrates such as rFVIIa, the use of these agents should be restricted to patients who meet the following criteria: life-threatening bleeding that is not related to a surgical source and is unresponsive to conventional therapy, such as platelets, plasma, and cryoprecipitate [2].
Cost is also an important issue, because the average annual cost of rFVIIa for non-approved uses within United States hospitals can exceed $500,000 annually. This is based on the cost of rVIIa, which ranges from $2,000 to $8,000 per dose. Medical oversight for rFVIIa utilization in non-approved settings has been shown to be effective in reducing the mean total dose of rFVIIa administered per patient from 8.2 ± 15.8 mg to 6.7 ± 5.2 mg, a savings of approximately $1,500 per treated patient [2]. A standard dose of 90 mcg/kg dose costs $5,000, which is four times the cost of full-dose aprotinin, an agent that is FDA approved for prophylactic administration to prevent bleeding in patients undergoing coronary revascularization. This is relevant because aprotinin has been shown to be effective (50% to 90% reduction in blood loss and transfusion as well as 70% reduction in re-exploration) and safe in several large, placebo-controlled, randomized trials [18]. Conceptually, use of rVIIa may be considered in the management of excessive bleeding after cardiac surgery related to preoperative clopidogrel use based on published evidence of excessive bleeding and transfusion in patients who are receiving clopidogrel; however, use of aprotinin should also be considered because recent evidence indicates that it may also be effective in this patient subset.
In summary, there are compelling data that off-label use of rFVIIa may be extremely useful in certain distinct settings such as first line therapy (ie, with intracranial hemorrhage) [3], life-threatening bleeding, or rescue therapy (ie, with excessive bleeding that is unresponsive to routine hemostatic therapy) [6]. It is intuitive that this agent may also be extremely useful in bleeding patients for whom no blood is available, who refuse blood, or for whom component therapy may not be effective (eg, platelet refractoriness). Randomized, controlled trials are warranted to assess the efficacy, safety, and cost-benefit of this intervention in cardiac surgical patients. In the meantime, this agent should be used sparingly and cautiously in non-life-threatening settings or as a prophylactic measure, especially in patients who are at increased risk for thrombotic complications.
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