Drug That Slows Bleeding Shows Off-Label Dangers

Link to New your Times Article


Published: April 18, 2011

A powerful, costly drug approved in 1999 for a small group of patients who may bleed uncontrollably during surgery is now used in a host of other surgical situations, sometimes with serious negative effects, two new studies report.

The studies present a cautionary tale, researchers say, that makes clear the pitfalls of a common medical practice – using new drugs in situations in which they have never been rigorously tested. The drug, sold as NovoSeven, was approved for people who lack a gene to make a particular blood-clotting protein called Factor VIIa and for certain people with hemophilia who can’t tolerate another drug that can stop bleeding.
The drug, which is Factor VIIa, is made by baby hamster kidney cells that have the gene for Factor VIIa added to them. The baby hamster cells secrete the protein into a solution containing newborn calf serum, and the protein is then extracted from that solution and purified. It takes a year to produce – most of that time, nine to 10 months, is devoted to testing the drug for purity and safety. The drug costs $10,000 a dose, but can be a lifesaver for these patients.
It is also used for other patients, according to the new studies, in The Annals of Internal Medicine. In fact, the small group for whom it was approved accounts for only 3 percent of the 18,000 times a year the drug is used in hospitals. Ninety-seven percent of the time when it is used in hospitals, it is given to patients with other reasons for bleeding, including having heart surgery or a hemorrhagic stroke, in which bleeding in the brain causes damage.
For such patients, one of the papers concluded, the drug not only fails to improve survival, it increases the likelihood of a blood clot in the heart or brain, resulting in a heart attack or the kind of stroke in which blood flow to a part of the brain is blocked. The drug is also used in trauma surgery, and in that use as well it fails to show improved survival. In trauma patients who receive the drug, however, there do not appear to be more clots than would otherwise occur.
“It’s scary,” said Dr. Jerry Avorn, a professor of medicine at Brigham and Women’s Hospital in Boston who wrote an editorial commenting on the studies. “This is a powerful drug, and we don’t fully understand it,” said Dr. Veronica Yank of Stanford, an author on both papers.
In heart surgery, the researchers report, one out of every 20 people given Factor VIIa would be expected to have a serious clot in the heart or brain. When the drug is used to control bleeding in or around the brain, as in patients suffering from hemorrhagic stroke, one out of 17 patients would get a dangerous clot at the higher dose that is often used and one out of 33 would get a clot in situations where doctors used a lower dose.
The clots, said Dr. Yank, can occur anywhere in the body, obstructing blood vessels. “Some patients got more than one clot,” she added.
Doctors say they give the drug because they can see an immediate effect: The bleeding stops. “It’s very dramatic,” said Dr. Mark Gladwin, chief of pulmonary and critical care medicine at the University of Pittsburgh Medical Center. And so, he added, “there is a very compelling motivation to use it.”
And the doctors who use the drug during surgery may not see a longer-term effect – clotting – which can occur days later. And they would have no way of knowing if the drug saves lives in the long run. Dr. Gladwin pointed out that doctors routinely administer drugs for unapproved uses.
Companies cannot promote drugs for such uses, but doctors are free to prescribe them. Novo Nordisk, the maker of the Factor VIIa drug, says that it does not promote unapproved uses and that it worked with the Food and Drug Administration to include warnings against such uses on the drug’s label.
As for the high cost, insurers pay for Factor VIIa as part of the general cost of treating hospitalized patients, so the drug may not be specifically identified. “Typically, the health plan would not know that it was used,” said Susan Pisano, a spokeswoman for America’s Health Insurance Plans, an industry group. Payment for Factor VIIa “would be part of a global payment,” she said.
Trauma surgeons were among the most enthusiastic early adopters of Factor VIIa, but they were also among the first to curtail use.
“I have used it, and virtually every trauma surgeon in the world who has access to it has used it,” said Dr. Ernest Moore, chief of surgery at Denver Health, an affiliate of the University of Colorado.
Many doctors got interested when they saw a paper, about a decade ago, describing an Israeli soldier who had a gunshot wound to the abdomen, got Factor VIIa, and was saved from what it seemed would have been certain death. In addition, research studies indicated that Factor VIIa was important in initiating clotting, giving credibility to the report.
As trauma surgeons began using the drug, Dr. Moore said, they had “the unforgettable experience of seeing people who were bleeding to death suddenly stop bleeding.” And, he added, “there is no question that in the right circumstances it can be a miracle treatment.”
But trauma surgeons’ unbridled enthusiasm for Factor VIIa was tempered recently when studies began to show no survival benefit.
He is using it less often now, as are many other trauma surgeons, Dr. Moore said. It is not clear that other medical specialties had a similar awakening, but some institutions, like the University of Pittsburgh Medical Center, have taken steps to control the drug’s use. The Pittsburgh hospital began requiring that doctors who wanted to use Factor VIIa get permission from a hematology consultant.
The one exception was patients who were bleeding into the brain, taking a blood thinner and about to have emergency neurosurgery. The consultants often refuse permission, said Dr. Franklin Bontempo, director of the coagulation laboratory at the University of Pittsburgh Medical Center.
Some doctors want to use it for routine bleeding in trauma patients or in patients having liver transplants. That is unnecessary, they often are told. Others call because a patient is bleeding into the lungs, coughing up blood, and the doctor is, quite understandably, worried, wanting to give Factor VIIa to make the bleeding stop. In that situation, Dr. Bontempo said, the hematologist will suggest other methods. “Often that takes care of the problem,” he said.
The lesson in the story of Factor VIIa, Dr. Yank said, is that anecdotal reports, even ones citing results as powerful as bleeding cessation, can be misleading. Using a drug for an unapproved use can be risky. A single measurement of outcomes can miss the big picture of risks and benefits. And the risk-benefit picture for the approved use may be quite different from what occurs when the drug is used in other situations
“You may be correct in assuming the drug has the same benefits,” Dr. Yank said, “but then again, you may not.”