Recombinant Activated Factor VII (rFVIIa) in the Treatment of Non-Hemophilia Patients: Physician Underreporting of Thromboembolic Adverse Events.

Background: Recombinant activated factor VII (rFVIIa) is a potent hemostatic agent with a short half-life of 2.6 hours and is approved for various hereditary and acquired bleeding disorders. Its “off-label” utilization has increased and is the focus of a number of ongoing clinical trials. One concern is that its beneficial hemostatic effect may be offset by the potential for thromboembolic adverse events (TAEs). Despite its short half-life, rFVIIa likely produces a sustained hemostatic effect and the potential for thromboembolic events may also be prolonged. A recent review of adverse events reported to the FDA suggested that this risk was substantial. The duration that this risk may be present is unclear. Physicians may only consider adverse events to be causally related in the immediate few hours after administration of rFVIIa leading to underreporting TAEs. We conducted a retrospective review of all off-label uses of rFVIIa comparing physician reporting of TAEs to documented TAEs on chart review.

Methods: Chart review of all non-hemophilia adult patients who had received rFVIIa at our tertiary care centre was completed. Following all off-label administration, questionnaires were routinely sent to all treating physicians to report outcomes and adverse reactions with the use of rFVIIa. We included all non-hemophilia adult patients at our tertiary care centre who have received rFVIIa. Exclusion criteria were age < 18 and patients with hemophilia or other bleeding disorders for which rFVIIa use is approved. TAEs identified during chart review were compared to physician reporting on questionnaires.

Results: A total of 71 patients, 32 females and 39 males, satisfied study criteria during the period January 1, 2003 to June 30, 2007. Mean age was 54 (range 18–84). This was a high-risk population with 34 (47.9%) deaths. Mean duration of follow-up was 30 days (within 1 day to 312 days). Total doses of rFVIIa administered ranged from 2.4–19.2mg (mean 8.2mg) given in 1 to 4 divided doses. 11 arterial and 5 venous TAEs identified on chart review were deemed possibly or probably related. These occurred on average 25 days (within 2 day to 89 days) after exposure to rFVIIa. In total, 50 physician questionnaires (70%) were completed. There were no TAEs reported to the transfusion safety officer at our institution by the treating physician(s) in these questionnaires.

Conclusions: Clinically important thromboembolic events due to recombinant activated factor VII are under-reported in this high-risk population. This review was not designed to determine if rFVIIa alters the rate of TAEs but emphasizes the need for careful follow-up, both immediate as well as longterm, of patients who have hemorrhage or are at risk of hemorrhage. Physicians treating patients with rFVIIa should be vigilant for potential TAEs beyond the immediate treatment period.