O'Connell KA, Wood JJ, Wise RP, et al. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA 2006;295:293-8.

In this article, the authors reviewed the serious adverse thromboembolic events attributed to the use of recombinant factor VIIa. From March 25, 1999, through December 31, 2004, a total of 185 thromboembolic events were reported to the FDA via the Adverse Event Reporting System (AERS). In 2004, over 40 thrombotic events were reported in 4520 hospitalized patients treated with recombinant factor VIIa. In an addendum to the article, an additional 61 thrombotic events were reported in the first 10 months of The vast majority of thromboembolic events were associated with the off-label use of this drug. These thrombotic events occurred when recombinant factor VIIa was given for surgery (either prophylaxis or bleeding), intracranial bleeding, and trauma. Alarmingly, 99 (54.1 percent) of these events were arterial. This includes 39 cerebrovascular accidents, 34 myocardial infarctions, and 26 other arterial thrombotic events involving large- and medium-size blood vessels. Venous clots accounted for another 40.4 percent of the thromboembolic events. The remaining 10 events included occlusion of extracorporal membrane oxygenation lines and dialysis shunts.

Recombinant human factor VIIa (NovoSeven) is FDA approved for controlling bleeding associated with inhibitors in patients with hemophilia A or B. It is also approved for treatment of patients with congenital factor VII deficiency. Through a series of case reports and a limited number of randomized trials, recombinant factor VIIa has been used to treat a wide variety of hemostastic abnormalities. These include coagulopathies associated with liver failure, trauma, hemorrhagic strokes, warfarin overdose, and surgical misadventures. These publications have created an impression that recombinant factor VIIa can function as a universal hemostatic agent, and that it is an appropriate supplement for treating the bleeding patient, regardless of the hemorrhagic etiology. Not only is this financially costly to society, this approach may also be costly to the patient's health.

A randomized placebo-control trial published one year ago in the New England Journal of Medicine1 tested the hypothesis that recombinant factor VIIa would be beneficial in the acute treatment of hemorrhagic strokes. In this study, it was noted that thromboembolic events were increased in patients randomized to receive recombinant factor VIIa. Most of these thrombotic events were arterial, and, notably, most were observed in patients who received the highest dose of recombinant factor VIIa. Novo Nordisk, the manufacturer of Novo Seven, issued a safety alert describing thromboembolic adverse events in non-hemophilia patients, and the FDA posted a safety alert on December 1, 2005.

Although the inclination is to attempt to use the data presented in O'Connell's article to calculate the incidence of thromboembolic complications resulting from recombinant factor VIIa therapy, it is impossible to use the AERS system for this purpose. The majority of thrombotic events detected under this system were spontaneously reported. As the authors acknowledge, underreporting is undoubtedly an issue when one relies on physician-initiated adverse event reports. Consequently, the true incidence of this dark complication of off-label use of recombinant factor VIIa therapy is unknown.

1.
Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005;352:777-

Competing Interests

Dr. Abrams indicated no relevant conflicts of interest.