Safety of recombinant activated factor VII in randomized clinical trials

N Engl J Med. 2010 Nov 4;363(19):1791-800. doi: 10.1056/NEJMoa1006221.


Background: The use of recombinant activated factor VII (rFVIIa) on an off-label basis to treat life-threatening bleeding has been associated with a perceived increased risk of thromboembolic complications. However, data from placebo-controlled trials are needed to properly assess the thromboembolic risk. To address this issue, we evaluated the rate of thromboembolic events in all published randomized, placebo-controlled trials of rFVIIa used on an off-label basis.

Methods: We analyzed data from 35 randomized clinical trials (26 studies involving patients and 9 studies involving healthy volunteers) to determine the frequency of thromboembolic events. The data were pooled with the use of random-effects models to calculate the odds ratios and 95% confidence intervals.

Results: Among 4468 subjects (4119 patients and 349 healthy volunteers), 401 [corrected] had thromboembolic events (9.0%). [corrected] Rates of arterial thromboembolic events among all 4468 subjects were higher among those who received rFVIIa than among those who received placebo (5.5% vs. 3.2%, P=0.003). Rates of venous thromboembolic events were similar among subjects who received rFVIIa and those who received placebo (5.3% vs. 5.7%). Among subjects who received rFVIIa, 2.9% had coronary arterial thromboembolic events, as compared with 1.1% of those who received placebo (P=0.002). Rates of arterial thromboembolic events were higher among subjects who received rFVIIa than among subjects who received placebo, particularly among those who were 65 years of age or older (9.0% vs. 3.8%, P=0.003); the rates were especially high among subjects 75 years of age or older (10.8% vs. 4.1%, P=0.02).

Conclusions: In a large and comprehensive cohort of persons in placebo-controlled trials of rFVIIa, treatment with high doses of rFVIIa on an off-label basis significantly increased the risk of arterial but not venous thromboembolic events, especially among the elderly. (Funded by Novo Nordisk.).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Factor VIIa / adverse effects*
  • Factor VIIa / therapeutic use
  • Hemorrhage / drug therapy*
  • Hemorrhage / etiology
  • Hemorrhage / prevention & control
  • Hemostatics / adverse effects*
  • Hemostatics / therapeutic use
  • Humans
  • Logistic Models
  • Middle Aged
  • Odds Ratio
  • Off-Label Use*
  • Randomized Controlled Trials as Topic
  • Thromboembolism / chemically induced*
  • Thrombosis / chemically induced*


  • Hemostatics
  • Factor VIIa