Six Year, Single Institution, off-Label Use of Recombinant Factor VIIa

Recombinant factor VIIa (rFVIIa) is used for hemophiliac patients with inhibitors against coagulation factor VIII or IX, but there is varied off-label use of rFVIIa for other patients. The aim of the present study was to examine our institution's off-label use of rFVIIa in an adult population.

We performed an IRB-approved retrospective review of rFVIIa administrations since its first use in January 2003 through December 2008. Patients were identified using an inpatient pharmacy database capturing all rFVIIa administrations. Blood product transfusion (packed red blood cells, pRBCs; fresh frozen plasma, FFP; platelets; cryoprecipitate), adjunctive hemostatic agent use (epsilon aminocaproic acid, protamine, desmopressin, estrogen, or vitamin K), and operative or vascular interventional procedures were examined before and after administration. Laboratory data including pH, temperature, prothrombin time (PT/INR), partial thromboplastin time (PTT), and fibrinogen were also collected by chart review. Outcome measures included mortality at 24h, 48h, and 30d, as well as thrombotic complications. Two-tailed paired T-tests were used for statistical comparisons.

A total of 256 consecutive adult patients received rFVIIa. Of these, 20 (8%) received rFVIIa for FDA-approved on-label use. Thus, 236 off-label rFVIIa administrations were confirmed, with an average patient age of 58± 19y.

The annual number of doses administered increased from 2003 to 2005, after which rFVIIa utilization remained constant (52 ± 5 patients/year from 2005–2008). rFVIIa was administered for head injury or hemorrhagic stroke (41%), cardiothoracic surgery (23%), gastrointestinal bleeding (14%), trauma (10%), off-label hematologic disorders (4%), vascular surgery (4%), transplantation (2%), orthopedics (2%), and obstetrics (2%). Administration locations consisted of the intensive care unit (70%), operating room (20%), emergency room (6%), and ward (2%). Single doses (79 ± 28 mcg/kg) comprised 79% of administrations. Extremely high and low single dose regimens (> ±1 standard deviation) were used in neurologic and cardiothoracic surgical populations. Immediately before rFVIIa administration, temperature was 36.9 ± 1.0 °C, pH 7.38 ± 0.10, platelets 141 ± 101 × 10⁹/L, PT/PTT 2.7/44 s, and fibrinogen 243 ± 131 mg/dL. These parameters did not clinically change at 24h or 48h after rFVIIa administration, though PT/INR stabilized at 1.28 ± 0.80 and 1.32 ± 0.41, respectively.

Mortality rates were 13%, 17%, and 38% at 24h, 48h, and 30d respectively. 80% of deaths at 24h were related to either uncontrolled or intracranial hemorrhage. 2 deaths >48h after administration were stroke related in a post-cardiopulmonary bypass setting. 25 thromboembolic complications occurred at any point following administration and through hospital discharge. Greater than 75% of the complications were deep vein thromboses, none resulting in death.

Of the 60 patients requiring massive transfusion (>10 pRBCs) in the 24h prior to rFVIIa administration, the pRBC, FFP and platelet usage significantly decreased within 24h (pRBC: 20.6 ± 9.9 to 8.4 ± 8.6; FFP: 12.0 ± 7.3 to 6.9 ± 8.1; platelets: 3.5 ± 2.8 to 2.1 ±2.0, all p<0.0001). 24h after rFVIIa in massively transfused patients, the number of patients requiring operation or vascular intervention procedures decreased from 27 to 14. This was also associated with a 38% decrease for the need of adjunctive hemostatic agents. There were no meaningful changes in laboratory coagulation parameters.

Analysis of this large retrospective cohort of single institution rFVIIa administration reveals 92% off-label use. The majority (64%) of indications are for cardiothoracic surgery and intracranial hemorrhage. Although thromboembolism rates are 10%, mortality at 24h does not seem to be associated with thromboembolism. In those requiring a massive transfusion, rFVIIa use may decrease transfusion requirements, need for operative or vascular intervention, and the need for hemostatic adjunct use.

Off Label Use: Recombinant factor VIIa and its off-label use in hemostasis. Lawson:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees.