Patients who received off-label recombinant activated factor VII for bleeding episodes had higher rates of arterial thromboembolic events than did those who received placebo, according to a pooled analysis of data from 35 clinical trials published Nov. 4 in the New England Journal of Medicine.
In particular, the rate of coronary arterial thromboembolic events was nearly three times higher in patients randomly assigned to receive rFVIIa off-label than in those assigned to placebo. The rate of adverse events also increased with advancing patient age and with higher doses of the drug, said Dr. Marcel Levi of the University of Amsterdam and his associates.
rFVIIa, marketed as NovoSeven by Novo Nordisk, is approved for the prevention or treatment of bleeding in patients with hemophilia or factor VII deficiency, but an increasing number of small studies have shown its usefulness for severe bleeding in other clinical conditions, including severe trauma, transplant surgery, intracerebral hemorrhage, and overreaction to anticoagulation therapy.
"Most of the safety data on off-label indications are retrospective and involve subjects [who already have] a relatively high risk of adverse events, including thrombosis, making interpretation of these findings difficult," Dr. Levi and his colleagues noted.
To better assess the drug’s thromboembolic profile, they pooled the data from 26 randomized, placebo-controlled trials involving 4,119 patients with a variety of clinical conditions and 9 randomized, placebo-controlled trials involving 349 healthy volunteers. A total of 29 of these 35 trials were sponsored by Novo Nordisk.
Most of these patients had spontaneous CNS bleeding (31%), advanced liver disease (28%), or trauma (19%). The mean age was approximately 51 years; some of the studies included children, including one that included infants.
Overall, the rate of thromboembolic events was 10.2% in subjects who received rFVIIa – significantly higher than the 8.7% rate in subjects who received placebo (N. Engl. J. Med. 2010;363:1791-1800).
Further analysis showed that almost all of this difference was caused by an excess of arterial thromboembolic events in those who received active treatment (5.5%), compared with those who received placebo (3.2%). There was no significant difference between the two groups in venous thromboembolic events.
Approximately 54% of the arterial thromboembolic events were coronary in nature. In this large subgroup of subjects, the rate of such events was almost three times higher in patients who received active drug, compared with those who received placebo.
The rate of arterial thromboembolic events increased with advancing patient age. In those older than 65 years the rate was 9% with the active drug, compared with 3.8% with placebo. In those older than 75 years the rate was 10.8% with the active drug and 4.1% with placebo. There also was a significant dose-dependent effect.
"This article should serve as a template for pharmaceutical companies to report all studies involving the use of a given drug, on-label and off-label, so that physicians can fully appreciate the benefit and risks when making therapeutic decisions," Dr. Louis M. Aledort wrote in an accompanying editorial (N. Engl. J. Med. 2010;363:1853-4).
"The authors appropriately warn readers that these data warrant scrutiny when rFVIIa is used on an off-label basis. The thrombolic sequelae reported here are not inconsequential," noted Dr. Aledort, professor of medicine, hematology, and medical oncology at Mount Sinai School of Medicine, New York.
The thrombotic risks associated with labeled indications for rFVIIa are low. In this study, the risks in healthy volunteers also were low. But for all other study subjects, the risks are substantially higher, even after adjusting for age and different types of bleeding, he wrote.
This pooled analysis was funded by Novo Nordisk, maker of NovoSeven. Dr. Levi’s associates in this study have ties to Norvo Nordisk or are employees and have equity interest in the company. Dr. Aledort reported ties to Baxter, CSL Behring, Grifols, Octapharma, Inspiration, GlaxoSmithKline, and Amgen.