The study, which appears in the Nov. 4 edition of the New England Journal of Medicine, sought to determine whether use of recombinant activated factor VII (rFVIIa) to treat life-threatening bleeding has been associated with an increased risk of thromboembolic (blood clotting) complications.
Recombinant activated coagulation factor VII (rFVIIa) is currently approved for the treatment of bleeding in patients with hemophilia A or B who also have inhibiting antibodies to coagulation factor VIII or IX. Indications have been broadened to include the treatment of episodes of bleeding and the prevention of episodes of bleeding related to surgical or invasive procedures in patients with congenital and acquired hemophilia or factor VII deficiency. According to study authors, including Jerrold Levy, MD, FAHA, professor and deputy chair for research, Department of Anesthesiology, Emory University School of Medicine, data from placebo-controlled trials were needed to properly assess clotting risk. To address this issue, researchers evaluated the rate of thromboembolic events in all published randomized, placebo-controlled trials of rFVIIa used on an off-label basis.
“The mechanism of action of rFVIIa may offer the potential for its use in preventing or treating severe or life-threatening bleeding in patients with other clinical conditions,” says Levy. “A growing number of case reports and small, controlled or uncontrolled studies have shown the successful use of rFVIIa for various clinical indications other than the treatment of hemophilia, including management of severe traumatic injury, control of bleeding during surgery and transplantation, treatment of intracerebral hemorrhage, and management of bleeding due to anticoagulation therapy.
“Many of the patients who have received rFVIIa for these indications have been at high risk for death or other adverse health event because of frank hemorrhaging, which was a prerequisite for the clinical trials.
Scientists analyzed data from 35 randomized clinical trials (26 studies involving patients and nine studies involving healthy volunteers) to determine the frequency of thromboembolic events. The data were then pooled with the use of random-effects models to calculate the odds ratios and 95 percent confidence intervals.
Among 4,468 subjects (4,119 patients and 349 healthy volunteers), 498 had thromboembolic events (11.1 percent). Rates of arterial thromboembolic events among all subjects were higher among those who received rFVIIa than among those who received a placebo. Rates of venous thromboembolic events were similar among subjects who received rFVIIa and those who received placebo (5.3 percent vs. 5.7 percent).
Among subjects who received rFVIIa, 2.9 percent had coronary arterial thromboembolic events, as compared with 1.1 percent of those who received a placebo. 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, and the rates were especially high among subjects 75 years of age or older.
Levy says that findings suggest that even though there are problems associated with rFVIIa, it should still be used off-label, with benefits that outweigh risks.
“Prohemostatic agents have potential risks- in fact some of the data includes multiply transfused patients, and transfusions are also associated with potential for adverse outcomes. Overall, you die from life threatening hemorrhage,” says Levy. “Thus, in patients with life threatening hemorrhage, the use of VIIa may be a life saving modality where the benefits of stopping bleeding outweigh the risks.”
In addition to Levy, other study authors included Marcel Levi, M.D., Henning Friis Andersen, M.Sc., and David Truloff, D.V.M.
The Robert W. Woodruff Health Sciences Center of Emory University is an academic health science and service center focused on missions of teaching, research, health care and public service. Its components include the Emory University School of Medicine, Nell Hodgson Woodruff School of Nursing, and Rollins School of Public Health; Yerkes National Primate Research Center; Winship Cancer Institute of Emory University; and Emory Healthcare, the largest, most comprehensive health system in Georgia. Emory Healthcare includes: The Emory Clinic, Emory-Children’s Center, Emory University Hospital, Emory University Hospital Midtown, Wesley Woods Center, and Emory University Orthopaedics & Spine Hospital. The Woodruff Health Sciences Center has a $2.5 billion budget, 17,600 employees, 2,500 full-time and 1,500 affiliated faculty, 4,700 students and trainees, and a $5.7 billion economic impact on metro Atlanta.