Safety of Recombinant Activated Factor VII in Randomized Clinical Trials

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), 498 had thromboembolic events (11.1%). 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 highest among subjects older than 65 years of age, as compared with those who were 65 years of age or younger (9.0% vs. 3.8%, P=0.003); the rates were especially high among subjects 75 years of age or older, as compared with those who were younger than 75 years of age (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.) N Engl J Med 2010;363:1791-800