Off-Label Use of Recombinant Factor VIIa in United States Hospitals: 2000-2008.

Abstract 67

Background: Recombinant factor VIIa (rFVIIa) is FDA-approved for treatment of bleeding due to factor VIII or factor IX inhibitors in the setting of congenital or acquired hemophilia or due to congenital factor VII deficiency. When first introduced into clinical practice in 1999, rFVIIa was used predominantly for these labeled indications. Over the years since it became widely available, rFVIIa has been employed extensively for off-label indications. The data to support these uses are sparse or, in some cases, contradictory.

Objective: To estimate patterns of off-label rFVIIa use in United States hospitals.

Data source: We evaluated data from the Premier Perspectives database of United States hospitals. This representative sample was used to extrapolate national usage patterns of rFVIIa. For each hospitalization at member institutions, the database includes information on patient demographics, primary and secondary diagnoses, medications dispensed, service items used, and disposition at discharge. We examined data encompassing hospitalizations between January 1, 2000 and December 31, 2008.

Results: Use of rFVIIa was reported in 235 of 615 hospitals (38%) in the Premier database. 12,644 hospitalizations involving administration of rFVIIa during the study period were identified. Based on statistical weights for each member hospital, this translates to an estimated 73,747 hospitalizations nationwide during which rFVIIa was employed, 18,311 (25%) of which occurred during 2008. Between 2000 and 2008, off-label use of rFVIIa increased more than 140-fold, such that in 2008, 97% of in-hospital indications were off-label. In contrast, in-hospital use for the hemophilias has increased 3.7-fold since 2000 and appears to have plateaued, such that on-label use accounted for only 4.2% of use overall and 2.7% of use in 2008. We found cardiac surgery (29% of use in 2008), trauma (28%), and intracranial hemorrhage (11%) to be the most common off-label indications for rFVIIa use. Consistent with the growth of these and other off-label indications, there has been a significant increase in the mean age of patients receiving rFVIIa from 3 years in 2000 to 59 years in 2008. Conditions with a prominent proportion of use in the elderly (>65 years) included aortic aneurysm (82%), prostatectomy (66%), brain trauma (64%), intracranial hemorrhage (58%), cardiac surgery (57%), and gastrointestinal bleeding (57%). Across all indications, in-hospital mortality has increased substantially over time from 5% in 2000 to 27% in 2008. The highest in-hospital mortality rates were associated with aortic aneurysm (57%), neonatal use (54%), variceal bleeding (51%), other liver disease (49%), liver biopsy (45%), vascular procedures (43%), intracranial hemorrhage (43%), brain trauma (40%), body trauma (36%), and gastrointestinal bleeding (35%). The population receiving rFVIIa for the most common indication, adult cardiac surgery, experienced 24% in-hospital mortality. Amongst all patients treated with rFVIIa in 2008, 43% were discharged to home. Most of the remaining patients were transferred to other facilities, including nursing homes, rehabilitation hospitals, and other acute care facilities. In contrast, hemophilia patients receiving rFVIIa experienced a 3.8% in-hospital mortality rate, while 85% were discharged directly home. Finally, we identified a significant shift in rFVIIa use from academic hospitals (89% in 2000) to non-academic hospitals (67% in 2008).

Conclusions: In hospitalized patients, off-label use of rFVIIa far exceeds use for the small number of licensed indications. Cardiac surgery, trauma, and non-traumatic intracranial hemorrhage represent the top indications for in-hospital rFVIIa use in the United States, together accounting for an estimated 12,448 of 18,311 (68%) uses during 2008. Across all off-label indications, in-hospital mortality is high, suggesting a substantial proportion of 'end-stage' use of rFVIIa. Use in such circumstances raises concerns about efficacy, associated adverse events, and allocation of resources. The marked shift in off-label use from academic to non-academic hospitals suggests wide acceptance despite these concerns. These patterns of expanding use are concerning given the absence of strong and consistent evidence to support the off-label application of rFVIIa.