Trauma Care May Be Killing Soldiers
ROBERT LITTLE
The Baltimore Sun
American military doctors in Iraq have injected more than 1,000 wounded troops with a potent and largely experimental blood-coagulating drug despite mounting medical evidence linking it to deadly blood clots that lodge in the lungs, heart and brain.
The drug, called Recombinant Activated Factor VII, is approved in the U.S. for treating rare forms of hemophilia that affect about 2,700 Americans. In a warning last December, the Food and Drug Administration said that giving it to patients with normal blood could cause strokes and heart attacks. Its researchers published a study in January blaming 43 deaths on clots that developed after injections of Factor VII.
The U.S. Army medical command considers Factor VII to be a medical breakthrough in the war, giving physicians a powerful way to control bleeding that can be treated otherwise only with surgery and transfusions. Guidelines at military field hospitals encourage its liberal use in all casualties with severe bleeding, and doctors in Iraq routinely inject it into patients upon the mere anticipation of deadly bleeding.
"When it works, it's amazing," said Col. John B. Holcomb, an Army trauma surgeon and the service's top advisor on combat medical care. "It's one of the most useful new tools we have."
Yet the Army's faith in the $6,000-a-dose drug is based almost entirely on anecdotal evidence and persists despite public warnings and published research suggesting that Factor VII is not as effective or as safe as military officials say.
Doctors and researchers at civilian hospitals, including major medical centers such as Johns Hopkins and Massachusetts General Hospital, have largely rejected it as a standard treatment for trauma patients. Other hospitals say they have grown increasingly cautious about administering it because of clots found in their patients, including some that have caused deaths.
Meanwhile, doctors at military hospitals in Germany and the United States have reported unusual and sometimes fatal blood clots in soldiers evacuated from Iraq, including unexplained strokes, heart attacks and pulmonary embolisms, or blood clots in the lungs. Some have begun to suspect Factor VII.
At the Walter Reed Army Medical Center in Washington, D.C., doctors said they tried to determine last year whether a seemingly high incidence of blood clots in their patients was related to Factor VII use in Iraq. However, they found that the Army was not collecting sufficient information about its use of the drug to draw any conclusions.
Doctors at the Landstuhl Regional Medical Center in Germany said they planned to track complications among war casualties who got Factor VII, after concluding that a heart attack in a patient last August was probably caused by the drug.
Fear of unwarranted risk
During one 24-hour period in May, while journalists for the Baltimore Sun were at the 10th Combat Support Hospital in Baghdad, three U.S. Army soldiers arrived in the emergency room with traumatic injuries, and all of them were injected with Factor VII. Two subsequently died, not from their battlefield injuries but from complications related to blood clots, according to medical records and interviews with doctors.
Some trauma and blood specialists outside the armed services think the military is taking an unwarranted risk with wounded soldiers because the drug has never been subjected to a large-scale clinical trial to verify that it works and is safe for patients without hemophilia.
"It's a completely irresponsible and inappropriate use of a very, very dangerous drug," said Jawed Fareed, director of the hemostasis and thrombosis research program at Loyola University in Chicago and a specialist in blood-clotting and blood-thinning medications.
"It's insane, using it that way. Absolutely insane," said Dr. Rodger L. Bick, a University of Texas hematologist and editor of the Journal of Clinical and Applied Thrombosis/Hemostasis.
Army trauma specialists say that blood clots in severely injured patients can be caused by many things and that using Factor VII is worth the risk.
But some civilian doctors who have worked with the drug say its clotting capabilities are so profound that they have to assume it is responsible for deaths among military casualties who have received it.
"Of course some of them are dying from it," said Dr. Louis M. Aledort, a professor of hematology at the Mount Sinai School of Medicine in New York who specializes in clinical research and who has studied Factor VII safety. "If you give people this kind of dangerous coagulating product, some of them are going to have [blood clots]."
Yet he and other civilian specialists were less troubled by the potential dangers, which they said might be justified given the severe injuries in Iraq, than by the lack of scientific evidence that war casualties are getting any benefit from taking the risk.
"If you don't have that," Aledort said, "then you're just experimenting on people with a dangerous drug."
Weighing side effects
Deciding what rate of complications is acceptable is a decision generally left to individual doctors. Officials at Novo Nordisk, the drug's manufacturer, say evidence of clot-related complications doesn't mean that Factor VII is too dangerous to use, only that the side effects need to be weighed against its potential to help a patient.
"It's really not a question of an absolute safety level, but rather a ratio of benefit to risk that has to be established," said Dr. Michael Shalmi, Novo Nordisk's vice president of biopharmaceuticals.
Military officials are unapologetic about moving aggressively toward a new treatment for the types of deadly bleeding they see frequently in Iraq. Wounded troops requiring transfusions of 10 or more units of blood have a 25% to 50% chance of dying from their injuries, they say, so anything that helps to stop severe bleeding is worth exploring.
"We're making decisions, in the middle of a war, with the best information we have available to us," said Holcomb, commander of the Army's Institute of Surgical Research.
As the trauma advisor to the Army surgeon general, Holcomb is largely responsible for establishing what types of drugs and equipment are used to treat wounded American soldiers. It was his decision, with the support of Army leadership, to begin using Factor VII as a standard treatment in Iraq.
The decision was made in February 2004, Holcomb said, after he saw results from the largest clinical trial conducted so far of Factor VII's use in trauma -- an international study of 277 people, sponsored by Novo Nordisk. It concluded that trauma patients who got Factor VII had the same likelihood of suffering blood clots as those who didn't. Those results, and data from a few much smaller studies that did not focus on trauma patients, made Holcomb comfortable that the drug was safe enough, he said.
The same study also suggested that Factor VII didn't work particularly well in trauma patients, especially those with penetrating injuries. But military doctors say they've since gathered enough hands-on evidence of the drug's effectiveness to continue promoting its use.
"I've seen it with my own eyes," said Air Force Lt. Col. Jeffrey Bailey, a trauma surgeon and senior physician at the American military hospital in Balad, Iraq. "Patients who are hemorrhaging to death, they get the drug and it stops. Factor VII saves their lives."
Doctors in Iraq's emergency rooms, however, almost never care for their patients long enough to see firsthand whether blood clots or other complications have developed. A typical war casualty treated at the hospital in Baghdad is flown to Balad within hours, then to Landstuhl in a day or less, then to the United States within another three or four days.
"I haven't noticed any complications, but then I wouldn't see them anyway," said Army Capt. David R. Steinbruner, an emergency room doctor who served at the Baghdad hospital. "They're usually gone by the next day."
Clots in the veins, including pulmonary embolism and a precursor called deep vein thrombosis, or DVT, are occasional complications of severe trauma regardless of whether Factor VII is used.Injured soldiers and Marines are particularly susceptible to such clots because they spend hours immobilized and unconscious flying from Iraq to Germany and the United States. Clots in the arteries, which flow outward from the heart and can lead to stroke and heart attack, are much less common.
But in the hospitals away from the front lines, military doctors tell anecdotes about patients with strange clots in their lungs or brains that defy obvious clinical explanation. Factor VII has become a prime suspect.
When researchers at Walter Reed studied cases of blood clots in 2003, before Factor VII was introduced in Iraq, they concluded that war casualties had the same frequency of complications as victims of civilian trauma.
A year later, the New England Journal of Medicine published a report on military care for the wounded, including the nine-month period after the Army had begun using Factor VII, and noted a "startling" rate of pulmonary embolism and DVT.
Doctors at Landstuhl began injecting every battlefield patient with an anti-coagulant drug in early 2005 because of the perplexing incidence of blood clots. They say that seemed to reduce the rates of pulmonary embolism, DVT and other clots in the veins.
But doctors say they also have seen war casualties in the last two years with unusual clots in their hearts and arteries that resemble complications found in elderly patients -- troubling, given that most patients at Landstuhl are in their 20s or 30s.
"We see some weird strokes," said Lt. Col. Warren Dorlac, director of trauma surgery and critical care at Landstuhl. "You can't draw any conclusions from one patient, but when you start to see [multiple cases], after a while you have to ask if something is wrong."
Even doctors who suspect a link between Factor VII and clot-related complications in a patient say they can't determine if there is a larger trend because the military doesn't keep enough information to study it.
Unexpected episodes
The Sun was able to identify a handful of wounded soldiers, either by witnessing their treatment in Iraq or reviewing their medical records weeks later, who were injected with the drug and later suffered unexpected episodes related to blood clots, including stroke, pulmonary embolism and heart attack.
Capt. Shane R. Mahaffee, wounded by a roadside bomb near Hilla, Iraq, on May 5, was injected with the drug in the emergency room and during surgery in Baghdad. Four days later, he suffered a pulmonary embolism -- a PE, in medical jargon. He died May 15 of infection and respiratory problems.
Pfc. Caleb A. Lufkin, 24, injured by a bomb May 4 in southern Baghdad and given Factor VII at the Baghdad hospital, suffered a blood clot in his lung two weeks later during surgery on his leg. The procedure was stopped; he was revived and placed on anti-coagulant drugs.
Lufkin died a week later during surgery. His autopsy report, obtained from his mother, says he might have died from an air bubble in his heart, but tests were not performed to confirm it and the surgery records indicate that doctors suspected a clot.
His official cause of death was "complications of blast injuries."
Doctors say that determining the precise cause of blood clots is rarely possible, making it difficult to establish definitively whether Factor VII is responsible for later complications. And military doctors caution against drawing any conclusions from individual cases.
"A year ago we had a 25-year-old patient, a burn patient, who had a heart attack, and he didn't get Factor VII," said Holcomb, considered one of the world's authorities on the use of Factor VII in trauma cases. "There are lots of complications occurring in this group of significantly injured young people. They have devastating injuries."
Military doctors in Iraq often inject Factor VII into injured patients in anticipation of coagulopathic bleeding later, but in hospitals in the United States it is more often used later in treatment, after other options have been tried, and only after case-by-case consideration.
"I want to hear about [the patient's] history, I want to know if they're at risk for thrombotic complications, and I want to know whether more routine measures that are medically appropriate have been exhausted," said Dr. Paul M. Ness, director of the transfusion medicine division at Johns Hopkins Hospital and a "gatekeeper" for Factor VII use there. "The problem is that we haven't seen any kind of good, randomized, controlled study showing us that the drug is safe and that it works."
"I think everyone has an anecdotal experience where it seemed to work dramatically in a patient," said Dr. John M. Harlan, chief of hematology/oncology at Seattle's Harborview Medical Center. "It's just that without the large, randomized trials, you can't identify those patients most likely to benefit. And, obviously, there are questions about adverse complications."
At Shock Trauma
Doctors at the R Adams Cowley Shock Trauma Center in Baltimore have been among the more prominent advocates for Factor VII in trauma patients, publishing several papers about the drug and documenting almost 300 uses since 2001.
When the FDA study questioning the drug's safety was published in January, the Shock Trauma doctors wrote a rebuttal letter and began sifting through their own data, expecting it to show that the potential for complications was overstated.
After reviewing each use at Shock Trauma over the last five years, however, doctors there realized that the data revealed an 8.7 percent rate of major clot-related complications.
Two young patients developed mesenteric ischemia, an interruption of blood flow to the intestines rarely found in patients younger than 60.
A woman developed a clot in the deep veins of an otherwise healthy leg.
One woman died of a heart attack minutes after being injected with the drug, and doctors later found a massive clot in her heart.
The survey identified 12 patients whose deaths were due, in part, to blood clots they suffered after getting Factor VII.
Doctors at Shock Trauma are still exploring Factor VII, but they say they are more cautious about who gets it. They have come to believe that Factor VII can cause cerebral and abdominal blood clots that they don't fully understand and that it should be used sparingly in patients without hemophilia.
"If you'd asked me a year ago, I would have told you the complication rate wasn't anywhere near 8 percent. But the data doesn't lie," said Dr. Thomas M. Scalea, the center's physician-in-chief.
Holcomb said that without a control group for comparison, the Shock Trauma data offers no new perspective on the safety of Factor VII. And he agrees that only a trial where patients are randomly given either the drug or a placebo can determine Factor VII's true rate of complications.
But Scalea thinks his results are "troubling," particularly considering the scarcity of sound research available and the lack of statistical evidence that Factor VII actually works.
"The data is the data, and nobody, to date, has been able to show an increase in survival," said Scalea.
"I think John Holcomb is an incredibly talented, tremendously bright guy who's had experiences I haven't had, and it's very possible that if I worked in John's environment I'd make the same decisions he's making.
"But I've had experiences he hasn't had. And in this environment we've become circumspect about Factor VII, in terms of its cost, its effectiveness and the rate of complications."
'Step back and ask'
The U.S. military has never performed the kind of retrospective analysis that the Shock Trauma center did, because it doesn't have the data available to do it.
Doctors in Iraq, Germany and the United States hold a conference call every Thursday to discuss patients they treated in recent days, in hopes of spotting issues and improving the system.
But with dozens of casualties evacuated from the war zone each week, the information can be overwhelming, particularly given the demanding nature of the work that military medical teams do every day.
When The Sun interviewed Gina Dorlac in late August, she had just awakened from a brief nap after an all-night shift during which nine war casualties were admitted to Landstuhl's intensive care unit. She joked that the workload and the long hours were reminiscent of her residency training. And she equated the perspective on patient care that the pace sometimes affords her to that of looking at the system through a microscope.
"You need someone outside of this kind of setting to be able to step back and ask those questions" about Factor VII, Dorlac said. "I don't know if they're doing that. I hope so."