Recombinant Factor VIIa: An Assessment of Evidence Regarding Its Efficacy and Safety in the Off-Label Setting

Abstract

Recombinant human factor VIIa (rFVIIa) is approved by the US Food and Drug Administration for use in the setting of hemorrhage associated with factor VIII or factor IX inhibitors in patients with congenital or acquired hemophilia. This indication represents only a small number of bleeding conditions. Since it became available, rFVIIa has been increasingly used in the management of off-label indications, ranging from emergent hemostasis in traumatic hemorrhage to prophylactic hemostasis in patients undergoing major surgery. Prominent off-label indications include the management of patients with coagulopathies, such as occurs in trauma patients experiencing massive and uncontrolled hemorrhage, and in patients undergoing cardiovascular surgery with cardiopulmonary bypass. Other occasions for use occur in patients with intact coagulation systems, with nontraumatic intracranial hemorrhage being the most common in this group. Uncertainties regarding the efficacy and safety associated with use of rFVIIa in these off-label scenarios have led to evidence-based assessments of patient outcomes, including mortality, the rate of thromboembolic adverse events, and posttreatment functional status. We review the evidence regarding the efficacy and safety of this important, but controversial, hemostatic agent in the off-label setting.

Bleeding and Clotting Disorders in Pediatric Liver Disease

“…The approved dose for inhibitor therapy in hemophilia is 90 g/kg/dose every 2 hours as needed, and for congenital FVII deficiency is 15-30 g/kg/dose every 4-6 hours until hemostasis is obtained. 66 Clinical trials of rFVIIa in the treatment of active bleeding in liver transplantation have used doses ranging from 20-120 g/kg/dose on varying schedules. [67][68][69][70] The clinical efficacy of rFVIIa in the treatment of cirrhotic patients with variceal bleeding has been studied in 2 randomized, doubleblinded trials by Bosch et al, which showed no overall effect of rFVIIa versus placebo and no significant differences in reported mortality, incidence of adverse events, or treatment failure.…”

“…75 Logan and Goodnough recommended that practicing hematologists exercise restraint in the use of rFVIIa in the off-label setting. 66 aPCCs contain FII, FVII, FIX and FX plus protein C, protein S, and traces of antithrombin, heparin, and vitronectin. These are pooled plasma products that have viral inactivation methods applied during their manufacture.…”

“…None showed any difference in mortality or thromboembolic adverse events (TAEs), and only one study showed a benefit of rFVIIa on decreasing RBC transfusion requirements. [66][67][68][69][70] Whereas rFVIIa has rarely been associated with TAEs when used for labeled indications, there has been concern with increased rates of TAEs with off-label use. A meta-analysis by Hsia et al of TAE rates across 22 clinical trials for various indications revealed a statistically significant increase in arterial thromboembolism, with a 4.5% rate in the rFVIIa-treated patients and a 2% rate with placebo.…”

Use of Recombinant Factor VIIa Utilization Among a Hospitalized Pediatric Population

“…There are no large efficacy studies evaluating rFVIIa dosage for off-label administration of rFVIIa in adults, much less children. Consequently, appropriate dosing regimens for off-label usage have not been well established with a wide range described in the literature (2). For example, doses of 5 -160 mcg/kg as a single dose or 45 -400 mcg/kg as a total rFVIIa dose have been reported for management of refractory bleeding following cardiothoracic surgery (4,6).…”

“…It functions via two separate mechanisms of action: 1) binding tissue factor (TF) released from subendothelium at sites of vascular injury, with subsequent activation of the common coagulation cascade and generation of activated factor X (FXa), activated factor V (FVa) and thrombin 2) binding activated platelets with surface bound FXa and FVa resulting in thrombin generation. Both mechanisms result in fibrin meshwork formation and clot stabilization at the region of endothelial disruption (1,2).…”