American military doctors in Iraq have injected more than 1,000 of the war's 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 only rare forms of hemophilia affecting 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 frontline physicians a powerful new means of controlling bleeding that can only be treated otherwise with surgery and transfusions. They have posted guidelines at military field hospitals encouraging its liberal use in casualties with severe bleeding, and doctors in Iraq routinely inject it into patients upon the mere anticipation of deadly bleeding to come.
"When it works, it's amazing," said Col. John B. Holcomb, an Army trauma surgeon and the service's top adviser 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 studying Factor VII, including the R Adams Cowley Shock Trauma Center in Baltimore, 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. And 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, but they discovered 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 plan to track complications among war casualties who got Factor VII, after concluding that a heart attack in a patient last August was likely caused by an injection of the drug in Iraq.
During one 24-hour period in May, while journalists for The 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 Dr. 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 could be caused by many things and that using Factor VII is worth the risk, considering reports from military doctors in Iraq describing its success at controlling severe bleeding.
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 the large group of 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 for taking the risk.
"If you don't have that," Aledort said, "then you're just experimenting on people with a dangerous drug."
'Benefit to risk'
Deciding what rate of complications is acceptable is generally left up 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 bleeding 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, vice president of biopharmaceuticals for Novo Nordisk.
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 percent to 50 percent chance of dying from their injuries, they say. And so anything that helps to stop severe bleeding is worth exploring, they say, even if it carries risk.
"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. "We're not waiting" for more clinical research, he said. "We'd still be talking about these things 10 years from now."
As the trauma adviser 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 doesn'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. Some say it's the best solution they've found for "coagulopathic" bleeding -- a particularly vexing type of hemorrhage in which a patient oozes blood even after surgical repair of his injuries. Without Factor VII, the only available treatment is blood transfusion, which they say doesn't always reverse the condition and can even make it worse.
"I've seen it with my own eyes," said Air Force Lt. Col. Jeffrey Bailey, a trauma surgeon deployed this summer as 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."
"I've never seen anyone have a stroke because of Factor VII. I've never seen anyone have a pulmonary embolism because of Factor VII," said Army Maj. Brett Schlifka, a neurosurgeon assigned this year to the Balad hospital. "But I've seen people who survived because of Factor VII."
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, and 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 Steinbruner, an emergency room doctor who served at the hospital in Baghdad. "They're usually gone by the next day."
Unwanted 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. And injured soldiers and Marines are particularly susceptible to such clots because they spend hours immobilized and unconscious flying from Iraq to the recovery hospitals in Germany and the United States. Clots in the arteries, which flow outward from the heart and can lead to stroke and heart attack when they are blocked, 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 any obvious clinical explanation. And 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 this time 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, and doctors there say that the effort seemed to reduce the rates of pulmonary embolism, DVT and other clots in the veins.
But doctors say they have also 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."
In early August, doctors at Landstuhl said they were worried by the case of a patient in his early 20s who suffered a heart attack while recovering from combat injuries. Federal privacy laws prohibit release of specific information about the patient, who survived, but doctors said they pored over his records for evidence of heart disease, coronary artery disease or some other explanation. The only thing that stood out was his injection of Factor VII in Iraq.
"He really scared me, because he didn't act the way he was supposed to act. There was no reason in the world why he should have had a heart attack," said Air Force Lt. Col. Gina Dorlac, the director of intensive care at Landstuhl, who treated the patient, and the wife of the hospital's trauma specialist. "The medicine was the only explanation that seemed likely."
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.
"To be honest with you, we've never looked, because we don't have the tracking system that covers everything that would be necessary to do that," Warren Dorlac said. "I think it's something we definitely need to look at."
Roughly 3 1/2 years after the war in Iraq began, the Department of Defense is only now beginning to implement a comprehensive computer system to record the treatments and outcomes for the 21,500 casualties from Iraq, about 6,500 of whom had injuries serious enough to require evacuation. Researchers are also trying to create a historical database using paper medical records, but it is a tedious process, and doctors say the accuracy and completeness of paperwork generated in a war zone are suspect.
As such, the military has no authoritative method of determining how many patients have received Factor VII and how many subsequently developed blood clots. Nor can it determine the rate of complications among patients who did not get the drug. Holcomb said that the military has administered the drug to more than 1,000 troops, and medical supply records from the Army show that the service has purchased the equivalent of about 2,000 standard doses since early 2004, but the Army doesn't keep track of how much has been administered.
And without computerized data, trends in the treatment of combat casualties are difficult to spot, military doctors say. Many physicians work only in Iraq or Germany for a few months before returning to non-combat jobs in the United States. And doctors outside Iraq say they don't always know which patients received Factor VII inside Iraq because complete medical records may not travel with each casualty from hospital to hospital. Patients occasionally arrive in Balad or Germany with notes from frontline surgeons written on their bandages.
Without hard evidence about Factor VII, military doctors say surgeons in Iraq -- "downrange," in military parlance -- are unlikely to worry about potential complications in light of the anecdotal evidence they see that the drug is working.
"Unless you have a formal policy, it's going to be pretty hard to convince surgeons downrange that they should stop using Factor VII because you're seeing a lot of clots. They'll say, `Well, I'm seeing a lot of bleeding,'" said Dr. William L. Jackson, a former intensive care physician at Walter Reed who left the Army in June to pursue a civilian medical practice.
"I really do think we do a good job by all of these soldiers and that they get excellent medical care. But figuring out something like whether Factor VII is hurting more people than it's helping is not the kind of thing that the Army does particularly well."
Others say that individual experience and anecdotes are shaky grounds on which to base medical decisions.
"To say that because you're in a war everything you do is right suggests to me a level of arrogance that can only lead to a poor outcome," said Dr. Andrew F. Shorr, formerly a pulmonary and critical care specialist at Walter Reed who recently left the Army and took a similar position at the Washington Hospital Center.
"Think about it. If you've got young soldiers having weirdo strokes, and you know they've been exposed to a drug like Factor VII, how long can you presume you don't have a safety issue? Just because you have the best of motives doesn't mean you don't have mediocre methods that are doing more harm than good."
Defense officials denied The Sun's request to review autopsy reports of soldiers killed in Iraq and Afghanistan, first on privacy grounds and then, when the newspaper requested the documents with names or other personal information removed, on the grounds that the reports contain intelligence that could be exploited by the military's enemies.
Three wounded soldiers
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, 36, wounded by a roadside bomb near Hilla, Iraq, on May 5, was injected with repeated doses of the drug in the emergency room and during surgery in Baghdad, and four days later he suffered a pulmonary embolism -- a PE, in medical jargon. He died May 15 of infection and respiratory problems.
"Had he not had that PE, he probably would have survived," said Warren Dorlac, who oversees all the trauma patients treated at Landstuhl. "The PE caused him to get intubated, and then get pneumonia, and then he spiraled downhill."
Pfc. Caleb A. Lufkin, 24, injured by a bomb on May 4 in southern Baghdad and given Factor VII immediately upon arrival at the Baghdad hospital, suffered a blood clot in his lung two weeks later during surgery on his leg. The procedure was stopped, and he was revived and placed on anti-coagulant drugs.
Lufkin died a week later, under similar circumstances, during a surgery that would not have been necessary if the blood clot hadn't stopped his earlier operation. His autopsy report, obtained from his mother, says he might have died from a bubble of air in his heart, although tests were not performed to confirm it and the surgery records indicate that doctors suspected a blood 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."
But doctors also said that some of the blood clots they have seen in war casualties from Iraq were likely side effects of Factor VII.
One case involved Sgt. Brandon Huff, who was given Factor VII in a combat support hospital in Mosul last year and later suffered a clot-related stroke. Huff, then 23, was injured on a foot patrol April 20, 2005, when a bomb amputated his left leg and peppered his abdomen with shrapnel.
According to his medical records, he had multiple operations and at least one dose of Factor VII while in Iraq, then was evacuated to Germany. When he woke up, doctors realized that he was paralyzed on his left side, and a scan revealed two blood clots in his brain. He survived, endured months of physical therapy, and has largely recovered.
A clot-based stroke in a 23-year-old man is such an oddity, even among patients with severe injuries, that doctors figured Huff's leg injury was the source of the clots -- even though veins in the legs lead to the heart and lungs, not to the brain. They assumed that Huff must have a congenital heart defect that allowed the clots to transfer across the chambers of his heart and into his arteries. Doctors performed an echocardiogram to confirm their suspicion, but the test was negative and showed Huff's heart to be normal and healthy.
Doctors interviewed by The Sun and told the details of Huff's case were at a loss to explain how a young man with none of the common risk factors for a clot-based stroke -- advanced age, high blood pressure, arteriosclerosis -- could suffer the kind of attack that typically afflicts the elderly.
"I would say it's very likely that stroke was caused by the Factor VII," said Bick, a professor of medicine and pathology at the University of Texas Southwestern Medical Center. "That's very unusual."
Military doctors are not the only ones using Factor VII "off-label" to treat patients with normal blood, going beyond the FDA-approved uses for hemophilia. The medical literature is rife with case studies from trauma centers throughout the world describing the drug's success in stopping bleeding when doctors had abandoned hope.
But use of the drug in civilian hospitals is limited by Factor VII's high cost -- a downside the Army can all but ignore. Factor VII is one of the most expensive drugs in the world, and the Army has bought roughly $11 million worth in the last three years.
Enthusiasm among civilian doctors has tempered for reasons beyond price, however, as research builds suggesting that Factor VII might be inducing unwanted clots and that it might not work as well as the anecdotal reports suggest.
While some small scientific studies suggest that bleeding trauma patients given Factor VII need fewer blood transfusions, none has recorded a statistically significant increase in survival among patients who get it. The study that documented the most promising use for Factor VII -- treating bleeding in the brain -- also reported a complication rate as high as 10 percent, compared with 2 percent for patients given a placebo.
When asked by Novo Nordisk to approve Factor VII for treating people without hemophilia, regulators around the world have indicated that they are concerned about Factor VII's potential for complications.
Novo Nordisk, which sells Factor VII under the brand name NovoSeven, sought permission in Europe to market the drug as a treatment for bleeding in the brain but withdrew the request in April after European regulators expressed concerns about "excessive clotting."
A report published early this year in the Journal of the American Medical Association, using data culled from the FDA's database of adverse drug reactions from 1999 to 2005, attributed 43 deaths to thrombo-embolism -- blood clots floating through the patients' veins or arteries -- after injections of Factor VII, mostly in patients without hemophilia.
The report offered no comparison with complication-free uses to put the deaths in perspective and could not prove that the drug caused the clots, and thus it had limited impact. But it was the first published report in a major medical journal to question the safety of Factor VII. And it suggested that the reports of adverse drug reactions filed with the FDA, which are required by drug manufacturers but voluntary for hospitals, "largely underestimate the actual number of occurrences."
Like virtually all published studies of the drug, the FDA report concluded that a large-scale clinical trial, in which 1,500 or more patients are randomly given either Factor VII or a placebo, is necessary to determine whether the drug is safe for non-hemophiliacs and whether it works. Because the FDA requires patient consent in clinical trials, which is often difficult to obtain from trauma patients, Novo Nordisk expects a large trial in the United States to take several years.
Civilian doctors contacted by The Sun, meanwhile, said they have largely abandoned their early hope that Factor VII would be safe and appropriate for widespread use. Most were surprised to learn that the military has embraced it so enthusiastically.
"It's very hard to justify that kind of use in any circumstance, military or non-military," said Dr. David Kuter, director of clinical hematology at Massachusetts General Hospital, who said his hospital mostly stopped using Factor VII for patients after noticing "an increased rate of death."
"There's just a lack of demonstrated efficacy in any situation," he said.
While they rarely see the types of complex injuries that Army doctors see, civilian doctors generally consider intravascular clots to be more dangerous than severe bleeding. Even patients who become "coagulopathic" -- who continue to bleed after their injuries are repaired surgically because their blood has lost the ability to clot -- have options available, including transfusions and other drugs. The effects of blood clots, however, can very quickly become irreversible and deadly.
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."