Background: FDA licensed recombinant human coagulation Factor VIIa (rFVIIa) in 1999 for bleeding in hemophilia A or B patients with inhibitors to Factors VIII or IX.  Post-licensure, there has been increasing use of rFVIIa in patients without hemophilia.

Methods: We reviewed thromboembolic adverse events (AEs) reported to FDA's Adverse Event Reporting System for rFVIIa through 2004.  Manufacturer reporting is mandatory, but reporting by clinicians and others is voluntary. Therefore, AERS is likely to under-represent actual events.  

Results: A total of 185 thromboembolic AEs among 168 patients receiving rFVIIa were reported to FDA; 59 of the 168 patients were enrolled in a post-marketing study.  Unlabeled indications accounted for 151 patients, including surgical procedures, intracranial hemorrhage, and others. Most patients were actively bleeding (n=115).  Reported AEs were thromboembolic cerebrovascular accident (n=39), myocardial infarction (n=34), other arterial thromboses (n=26), pulmonary embolism (n=32), other venous thromboses (n=42), and clotted devices (n=10). In 36 of 50 deaths, the probable cause (from autopsy or clear clinical data) was the thromboembolic event. In 144 patients with timing information, 73 events occurred in the first 24 hours (30 within 2 hours).  Pro-coagulant concomitant medications were identified in 64 patients. 

Conclusions:  Most reported thromboembolic AEs followed the use of rFVIIa for unlabeled indications, often resulting in serious morbidity and mortality.  However, evaluation of the reports is confounded by underlying diagnoses, concomitant medications, pre-existing conditions, and inherent limitations of passive surveillance.  Randomized clinical trials designed to establish the safety and minimum effective dose in patients without hemophilia are needed.