Recombinant factor VIIa: Off-label use poses danger

June 15, 2011

Are surgeons at your hospital using recombinant factor VIIa to control bleeding? If so, they are probably not helping patients and could be harming them.

Key Points

Are surgeons at your hospital using recombinant factor VIIa (NovoSeven RT Coagulation Factor VIIa [Recombinant] Room Temperature Stable, Lyophilized Powder, Novo Nordisk) to control bleeding? If so, they are probably not helping patients and could be harming them. New data show that about 97% of hospital use of the drug is off label and the effects are somewhere between useless and potentially fatal.

"For the labeled indications, the control of bleeding in hemophilia, the evidence is pretty clear," Veronica Yank, MD, told Drug Topics. Yank is lead author of a review of NovoSeven sponsored by the Agency for Healthcare Research and Quality (AHRQ). "For off-label use, there are no indications that it reduces mortality and strong evidence that it leads to increased rates of thromboembolism. We found no evidence to suggest that the drug saves lives for any of the patient scenarios or conditions that we evaluated."

Dr. Yank is a postdoctoral research fellow and instructor at Stanford Medical School, Stanford, Calif. The article appeared in Annals of Internal Medicine in April.

Off-label use examined

AHRQ asked Stanford's Prevention Research Center to evaluate the off-label use of NovoSeven, Dr. Yank said. The agent was approved in early1999 for use in patients with hemophilia A or B and antibody inhibitors against standard-factor replacements. A tide of anecdotal reports from military and civilian surgeons cast the drug as a miracle clotting agent. It carries a black-box warning of serious thrombotic adverse events when used off label.

According to Novo Nordisk spokesman Ken Inchausti, 2010 sales of NovoSeven were approximately $1.5 billion, with use primarily occurring in hospital or inpatient treatment settings. Originally, the agent was approved as an orphan drug. It costs between $5,000 and $10,000 per use, depending on patient and dosing.

"We hope the Annals article and some of the other AHRQ materials will empower hospitals and hospital pharmacists to have conversations at the top levels to deal with the problem before it comes up," Dr. Yank said.

Hospitals take steps

Some hospitals have already tackled the problem. "Our trauma surgeons use factor VIIa all the time when patients are bleeding out," reported Krista Luck, PharmD, CPP, clinical coagulation specialist at Mission Hospital, Asheville, N.C. "We no longer use factor VIIa for warfarin reversal because there were too many side effects. When we took the data to our ER doctors, they stopped using it without a question. Vitamin K and other hemostatic agents are more useful and don't produce the kind of life-threatening clotting you can see with factor VIIa."

Dr. Luck said that pharmacists are taking the same message about clotting dangers to surgeons. Pitting clinical evidence of no benefit and potential harm against anecdotal reports of miracle cures is a tough job. Most of the education has to be done through practice committees and formulary decisions, she said. Routing all orders through the electronic prescriber order entry system helps boost formulary compliance and limit factor VII use.

Surgeons see only the benefits

One problem is that surgeons see only the beneficial effects of factor VIIa, Dr. Yank said. It can stop bleeding so quickly that it almost seems like a miracle. What surgeons don't see are the embolisms that develop a day or two later.

Educational materials for clinicians and policy makers can help, she continued. AHRQ's Evidence-Based Practice center links to a variety of materials, including 1-page handouts and evidence reviews.

"You need to look at the bigger picture, not just what happens in surgery," she said. "Mortality and long-term clinical outcomes are part of the decision to use any drug. We all recognize that there are some very good reasons to use certain agents off label under some conditions. But you should be wary. The better the anecdotal reports sound, the more cautious you need to be."