Safety of Recombinant Activated Factor VII in Randomized Clinical Trials

N Engl J Med
Marcel Levi, M.D., Jerrold H. Levy, M.D., Henning Friis Andersen, M.Sc., and David Truloff, D.V.M.
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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.
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.
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 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).
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.)

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