Bleeding is a problem faced by physicians, surgeons, and other health care providers on a daily basis. We constantly puncture arteries and veins for blood specimens and sever subcutaneous blood vessels with incisions. We sometimes take for granted the ability of the body to stop bleeding. However, in practicing medicine, we are also exposed to exceptional situations that require mechanism-based approaches to manage bleeding. To what does one resort when pressure, cautery, and hemostats are not enough? How do you stop a hemorrhage that you cannot reach? When I start my neurology residency in a year’s time, I might face a similar question: what can I do to slow or stop an intracerebral hemorrhage (ICH) that the neurosurgeons cannot safely reach?
During the past decade, some physicians have inferred from clinical experience that recombinant activated coagulation factor VII (rFVIIa) may work as an effective treatment for acute, severe bleeding episodes of a variety of origins. Originally developed as an alternative approach to treating hemophilia due to factor VIII and factor IX deficiencies when such patients had developed neutralizing antibodies because of multiple transfusions of clotting factors, rFVIIa proved useful in a variety of off-label bleeding situations. However, the risk of unintended thrombo-embolic events (TEs) as a result of administering the coagulation factor was not clear: the rate of TEs in patients with hemophilia treated with rFVIIa was relatively low at 1-2%, but it was not known whether this could be extrapolated to other patients treated with rFVIIa for off-label uses such as intracerebral hemorrhages, severe traumatic injury, surgery, or bleeding in the setting of anticoagulation therapy or advanced liver disease.
To assess this risk in their study, “Safety of Recombinant Activated Factor VII Based on Randomized Clinical Trials,” Levi et al. collected data from 35 randomized trials in which rFVIIa was used off-label to treat severe bleeding episodes in patients without hemophilia (31.3% for ICH, 27.8% for advanced liver disease, 18.7% for trauma) or in healthy volunteers to test the ability to reverse anticoagulation therapy. The authors discovered that the rate of arterial TEs was significantly higher in patients treated with rFVIIa (5.5%) as opposed to placebo (3.2%, p=0.0025), and most of these TEs involved the coronary circulation (53.9%). Rates of arterial TEs were higher among older patients (age > 65 years). There was no significant difference in rates of venous TEs between the two groups.
In summary, the use of recombinant factor VIIa in patients without hemophilia treated for severe bleeding episodes does confer an increased risk of unintended arterial thromboembolism, but there may still be situations where the potential benefits of treatment outweigh the risk.
In an accompanying editorial, Dr. Louis Aldort from the Mount Sinai School of Medicine adds, “This article should serve as a template for pharmaceutical companies to report all studies involving the use of a given drug, on-label and off-label, so that physicians can fully appreciate the benefit and risks when making therapeutic decisions.”
Have you used recombinant factor VIIa for an off-label use to stop severe bleeding in a patient? Will this risk assessment modify your use of this medication or your strategies for hemostasis?