April 21, 2011 — A new study finds that in the United States, recombinant factor VIIa (rFVIIa; NovoSeven, Novo Nordisk) is only rarely used for what it is specifically approved for — treatment of bleeding in patients with hemophilia A or B, and as an antibody inhibitor against standard-factor replacements.
Instead, the drug is far more likely to be used for the off-label treatment of, or prevention of, bleeding in other conditions, such as cardiovascular surgery and body and brain trauma, according to a study published in the April 19 issue of the Annals of Internal Medicine.
"There is troubling, widespread off-label use of rFVIIa in US hospitals," the study team concludes.
A second study also published in the April 19 issue of the journal finds that off-label use of rFVIIa is not beneficial, and may be harmful.
In a linked commentary, Jerry Avorn, MD, and Aaron Kesselheim, MD, JD, MPH, from Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, say the research provides "compelling data" on the rapidly increasing use of an expensive treatment that does not benefit patients and increases the risk for dangerous thrombotic events.
140-Fold Increase in Off-Label Use
In the first study, first author Aaron C. Logan, MD, PhD, and colleagues from Stanford University in California reviewed hospital records for 12,644 US patients who received rFVIIa during a hospital stay between January 1, 2000, and December 31, 2008.
They report that the use of rFVIIa in hospitalized patients without hemophilia grew more than 140-fold during the 9-year period, such that by the end of 2008, 97% of 18,311 in-hospital uses were off-label (95% confidence interval [CI], 96% - 98%). In contrast, in-hospital use for the approved indication (hemophilia) increased less than 4-fold and accounted for only 2.7% of its in-hospital use (95% CI, 1.9% - 3.5%).
One of the most common off-label uses was for cardiovascular surgery (29%; 95% CI, 21% - 33%) in both adults and children. "In 2008, more than 1 in 4 patients who received rFVIIa were treated in the context of cardiovascular surgery," despite "limited evidence to support this use," the authors note.
The other most common off-label uses were for body and brain trauma (29%; 95% CI, 19% - 38%) and intracranial hemorrhage (11%; 95% CI, 7.7% - 14%).
In general, report Dr. Logan and colleagues, "use of rFVIIa is growing in the absence of clear evidence of therapeutic efficacy and without close surveillance for associated harms." In the nationwide sample of hospitals they analyzed, in-hospital mortality for rFVIIa-treated patients was high, at 27% overall, and as high as 40% to 50% for several indications, they report.
Support for Off-Label Use Lacking
In the second study, first author Veronica Yank, MD, from Stanford University, who also worked on the other study, and colleagues systematically reviewed the literature on the efficacy and safety of rFVIIa used for 5 unapproved indications: intracranial hemorrhage, adult cardiac surgery, trauma, liver transplantation, and prostatectomy.
They found 64 studies from 62 articles that they deemed worthy of review and that had been published up to 2010. Most were observational studies either with a comparator (n = 26) or without (n = 22). Only 16 studies were randomized controlled trials. There was "great variability" in rFVIIa doses administered (range, 5 - 400 μg/kg).
For intracranial hemorrhage, mortality was not reduced with rFVIIa use across a range of doses, and arterial thromboembolism was increased with medium-dose rFVIIa use (risk difference [RD], .03; 95% CI, .01 - .06) and high-dose rFVIIa (RD, .06; 95% CI, .01 - .11).
There was also no mortality benefit with use of rFVIIa for adult cardiac surgery, but there was an increased risk for thromboembolism (RD, .05; 95% CI, .01 - .10). For body trauma, there were no differences in mortality or thromboembolism, but there was a reduced risk for acute respiratory distress syndrome (RD, −.05; 95% CI, −.02 to −.08).
There was only 1 randomized controlled trial on prophylactic use of rFVIIa in patients having prostatectomy, and mortality and thromboembolic events could not be evaluated because of limited events, the researchers say.
Action Needed to Curb "Runaway" Use of rFVIIa
In their commentary, Dr. Avorn and Dr. Kesselheim suggest that hospitals and the US government take measures to prevent the "runaway" off-label use of this expensive treatment, including greater oversight in hospitals and legal action, should evidence emerge that the manufacturer played an active role in building a market for off-label use.
The editorialists emphasize that it is not yet clear whether improper promotion of rFVIIa contributed to its rapid increase in use, although the US Department of Defense is said to be looking into it, according to a May 16, 2010, article published in the Baltimore Sun. The company has denied such practices.
The "good news," Dr. Avorn and Dr. Kesselheim say, is that both of these studies were made possible by funding the Agency for Healthcare Research and Quality (AHRQ), "which is devoting increasing resources to support such comprehensive assessments of both utilization and of efficacy and safety — the sine qua non of a data-driven health care enterprise."
"These studies provide rigorous, unbiased assessments of both utilization patterns and clinical evidence that can serve as a model for the many other issues of rational therapy decisions that physicians, patients, and policymakers face," they write.
The 2 studies were supported primarily by the AHRQ, US Department of Health and Human Services. The National Heart Blood and Lung Institute and the Palo Alto Medical Foundation Research Institute also supported the second study. Several of the authors have received grant money (to their institution) from the AHRQ. Randall S. Stafford, MD, PhD, an author on both studies, discloses having provided expert testimony to Mylan Pharmaceuticals and grant funding from the National Heart Blood and Lung Institute . One author from the second study received consultancy fees from Sanofi-Aventis, as well as grant support from the US Department of Veteran’s Affairs. Dr. Kesselheim has received grant money to his institution from AHRQ and the Robert Wood Johnson Foundation. Dr. Avorn has disclosed no relevant financial relationships.
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