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Kathryn A. O’Connell, MD, PhD; Jennifer J. Wood, PhD, MPH; Robert P. Wise, MD, MPH; Jay N. Lozier, MD, PhD; M. Miles Braun, MD, MPH

JAMA. 2006;295:293-298.

Context  The US Food and Drug Administration (FDA) licensed recombinant human coagulation factor VIIa (rFVIIa) on March 25, 1999, for bleeding in patients with hemophilia A or B and inhibitors to factors VIII or IX. Use in patients without hemophilia has been increasing since licensure.

Objective  To review serious thromboembolic adverse events (AEs) reported to the FDA's Adverse Event Reporting System (AERS).

Design, Setting, and Patients  The AERS database was reviewed from March 25, 1999, through December 31, 2004, for thromboembolic AE reports with rFVIIa. The AERS database includes US and non-US spontaneous AE reports from both approved (specific indications for patients with hemophilia) and unlabeled uses. It also includes serious AEs in patients enrolled in postlicensure clinical trials who received rFVIIa. Manufacturer reporting to FDA is mandatory, but primary notification from clinicians and others to FDA or manufacturers is voluntary for spontaneous reports; therefore, AERS underrepresents actual event occurrences.

Main Outcome Measure  Reported thromboembolic events occurring in patients administered rFVIIa.

Results  A total of 431 AE reports for rFVIIa were found, of which 168 reports described 185 thromboembolic events. Seventeen events occurred in patients with hemophilia and 59 occurred in patients enrolled in postlicensure trials. Unlabeled indications accounted for 151 of the reports, most with active bleeding (n = 115). Reported AEs were thromboembolic cerebrovascular accident (n = 39), acute myocardial infarction (n = 34), other arterial thromboses (n = 26), pulmonary embolism (n = 32), other venous thromboses (including deep vein thrombosis) (n = 42), and clotted devices (n = 10). In 36 (72%) of 50 reported deaths, the probable cause of death was the thromboembolic event. In 144 patients with timing information, 73 events (52%) occurred in the first 24 hours after the last dose (30 events within 2 hours). Sixty-four reports (38%) noted concomitant use of hemostatic agents. Most reports lacked sufficient information to evaluate potential dosage associations.

Conclusions  Most reported thromboembolic AEs followed the use of rFVIIa for unlabeled indications and occurred in arterial and venous systems, often resulting in serious morbidity and mortality. Analysis of the relationship between AEs and rFVIIa is hindered by concomitant medications, preexisting medical conditions, confounding by indication, and inherent limitations of passive surveillance. Randomized controlled trials are needed to establish the safety and efficacy of rFVIIa in patients without hemophilia.

Author Affiliations: Division of Epidemiology, Office of Biostatistics and Epidemiology (Drs O’Connell, Wood, Wise, and Braun), and Division of Hematology, Office of Blood Research and Review (Dr Lozier), Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Md. Dr Wood is now with the Cordis Corporation, Miami Lakes, Fla.

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