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), 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.).
Department of Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. m.m.levi@amc.uva.nl
Marcel
M
Levi
Jerrold H
JH
Levy
Henning Friis
HF
Andersen
David
D
Truloff
D000328:Adult; D000368:Aged; D015942:Factor VIIa / Q000009:adverse effects* / Q000627:therapeutic use; D006470:Hemorrhage / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control; D006490:Hemostatics / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D016015:Logistic Models; D008875:Middle Aged; D016017:Odds Ratio; D056687:Off-Label Use; D016032:Randomized Controlled Trials as Topic; D013923:Thromboembolism / Q000139:chemically induced*; D013927:Thrombosis / Q000139:chemically induced*
D006490:Hemostatics; D015942:Factor VIIa