Use of Off-label Recombinant Activated Factor Seven for Uncontrolled Bleeding

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Abstract

This protocol was a chart review of the NIH Clinical Center's off-label use of rFVIIa for uncontrolled bleeding. rFVIIa is a prohemostatic agent that was first approved by the FDA in 1999 for use in patients with hemophilia A or B that have factors VIII or IX inhibitors. Since its introduction onto the market, other uses for rFVIIa have been explored, including use in patients with other coagulopathies or patients with normal coagulation that have uncontrolled or life-threatening bleeding, such as in trauma or intracerebral hemorrhage. Currently, off-label use of rFVIIa accounts for the majority of its use in the United States. Recently, several studies and meta-analyses of rFVIIa therapy for unapproved conditions have demonstrated minimal efficacy and possible harm from thrombotic complications in certain patient populations. At the NIH, we have a unique experience with the use of rFVIIa and have frequently used this medication off-label. Many of our patients are hematopoietic stem cell transplant recipients or have underlying disorders of hematopoiesis that impair their ability to achieve adequate hemostasis or make them prone to episodes of uncontrolled bleeding. Only limited data exists evaluating the use of rFVIIa in hematopoietic stem cell transplant recipients. The study will be limited to a review of patient medical records. This chart review began in the fall of 2011 and be completed by August 2013. We have identified all patients who have received rVIIa at the Clinical Center from 2003 to 2012. We also added hematopoietic stem cell transplant subjects who developed DAH who did not receive rFVIIa, which allowed us to compare clinical outcomes in patients who did not receive rFVIIa versus those that did receive rFVIIa. We performed a retrospective cohort analysis to assess the benefits and risks of recombinant human factor VIIa (rFVIIa) as a therapeutic adjunct for alveolar hemorrhage (AH). Between 2005 and 2012, 57 episodes of AH occurred in 37 patients. Fourteen episodes (in 14 patients) were treated with steroids alone, and 43 episodes (in 23 patients) were treated with steroids and rFVIIa. The median steroid dose was 1.9 mg/kg/d (interquartile range IQR, 0.8 to 3.5 mg/kg/d; methylprednisolone equivalents) and did not differ statistically between the 2 groups. The median rFVIIa dose was 41 g/kg (IQR, 39 to 62 g/kg), and a median of 3 doses (IQR, 2 to 17) was administered per episode. Concurrent infection was diagnosed in 65% of the episodes. Patients had moderately severe hypoxia (median PaO2/FiO2, 193 IQR, 141 to 262); 72% required mechanical ventilation, and 42% survived to extubation. The addition of rFVIIa did not alter time to resolution of AH (P=.50), duration of mechanical ventilation (P=.89), duration of oxygen supplementation (P=.55), or hospital mortality (P=.27). Four possible thrombotic events (9% of 43 episodes) occurred with rFVIIa. rFVIIa in combination with corticosteroids did not confer clear clinical advantages compared with corticosteroids alone. In patients with AH following hematopoietic stem cell transplantation, clinical factors (i.e., worsening infection, multiple organ failure, or recrudescence of primary disease) may be more important than the benefit of enhanced hemostasis from rFVIIa. This study is now completed.