Dangerous Gamble

Dec. 5, 2006 — -- U.S. military doctors are using a controversial drug in a setting unmatched by any U.S. civilian hospital -- while civilian doctors in hospitals across the country are carefully watching to see whether the military is blazing a new life saving frontier or subjecting badly injured soldiers to a drug that may be doing more harm than good.

Trauma surgeons on American soil use the same drug on civilians, with only anecdotal evidence to suggest that the drug isn't causing harm to patients who are sometimes at death's doors when the drug is administered.

The question is, knowing its potentially deadly risks, is the use of this drug a responsible medical move?

Off-Label Use a Usual Tactic

Recombinant Factor VIIa -- or rF7a, sold as NovoSeven -- is a blood-clotting medication approved by the FDA only to control bleeding episodes in some hemophiliacs and in patients whose bodies don't make natural rF7a.

The drug is designed to work with the body's own blood-clotting machinery to slow down and stop uncontrolled bleeding in hemophiliacs. It is not FDA approved to stop uncontrolled bleeding in soldiers who have suffered blast wounds, or in civilians caught in car crashes or gunfire, but that's exactly how doctors in Iraq and the United States have been using it.

To use a drug for any use other than that for which it has been approved is called off-label use. Off-label use is very common in medicine -- but can be very risky.

In the case of rF7a, the very things that make the drug work for hemophiliacs also make it risky -- or potentially deadly -- for anyone else.

"Because rF7a works by activating the body's blood-clotting system, a potential risk is clotting at sites other than the injury [thromboembolism]," said Paul Richards, an FDA spokesman.

The FDA and the drug maker, Novo Nordisk, warned doctors in 2005 that the rF7a could potentially increase the risk of blood clots and complications from blood clots in nonhemophilia patients.

"The moment [rF7a] reaches the bloodstream, it triggers clotting," said Jawed Fareed, a pharmacologist and director of the hemostasis and thrombosis research program at the Loyola University Stritch School of Medicine in Loyola, Ill.

That means rF7a could cause strokes, heart attacks or worse. That danger might be even greater in trauma patients -- especially military trauma patients -- where splintered bone fragments attract blood factors that increase the risk of blood clots. But doctors have no evidence now that the drug is in fact causing harm to patients -- nor do they have conclusive evidence of the drug's benefits.

The very population in which the drug is being used is an at-risk population. Trauma victims are already at a high risk of developing clots and pulmonary emboli just by the nature of their injuries.

Medicine in a Time of War

The military's use of rF7a -- as it was recently described in a series of articles by Baltimore Sun reporter Robert Little -- embraces those potential risks in favor of the possible benefits to wounded troops.

Roughly 5 percent to 10 percent of soldiers brought into military trauma wards are treated with aggressive treatment guidelines that include giving rF7a.

Civilian hospitals in the United States use rF7a off-label only as a last resort, but military hospitals are very different from civilian hospitals. They see vastly different degrees of trauma. Combat hospitals are in a war zone. Civilian hospitals are not.

Trauma surgeons at combat support hospitals see soldiers who have been hit by roadside bombs, improvised explosive devices (IEDs), or worse. Patients arrive suffering multiple kinds of serious trauma wounds -- what doctors refer to as blunt and penetrating trauma.

Blunt trauma is like what a civilian would suffer in a car accident. Penetrating trauma is like a stab wound. Typically, civilians suffer one or the other.

"The most common injury you see in Iraq is a wounded soldier after a truck explosion," said Dr. Martin Lucenti, director of clinical operations at Northwestern Memorial Hospital in Chicago and a member of the Vermont Army National Guard.

"The truck flips and becomes shrapnel, so the soldier suffers the impact of the explosion plus bullet wounds from propelled vehicle fragments. Then the truck catches on fire, so the soldier suffers burns," he said.

"These are horrible, horrible injuries that you don't typically see in the U.S." said Lucenti, who recently returned from a three-month stint at the 10th Combat Support Hospital in Baghdad.

The key question in the military usage of this drug is not whether U.S. troops are suffering life-threatening injuries, but whether the risks of rF7a outweigh the benefits of giving it in these life-threatening situations.

The question is virtually impossible to answer definitively. Doctors and scientists have never studied the long-term effects of rF7a on trauma victims, or the difference between trauma patients who are and are not treated with rF7a and their survival rates and rates of complications.

It saves lives, say some doctors who have seen the drug in action. Other doctors suggest that soldiers have died unnecessarily because of it. Only scientific data could provide a definitive answer, but doctors and families only have stories to tell to support their opinions. In that respect, rF7a is stuck in a "he said, she said" debate.

The U.S. military is now at the forefront of that debate. As of right now, it doesn't have a definite answer, either.

The U.S. military does say, they do have data to support the use of rF7a. "Our preliminary analysis of cases at Landstuhl Regional Medical Center has also shown no increase in complications attributable to this drug in our trauma patients," said Col. Paul Cordts, a vascular surgeon for the Army.

ABC News has not seen this analysis.

On the Front Lines

In military hospitals, rF7a is given to Americans and Iraqis as part of treatment guidelines developed by Col. John Holcomb, M.D., commander of the U.S. Army Institute of Surgical Research. Acting from Holcomb's guidelines, military doctors treat patients aggressively and with very standard blood products they have at their disposal: whole blood, fresh frozen plasma, platelets, all products that are known to be safe and somewhat effective.

Guidelines also call for rF7a in high and multiple doses.

The treatment guidelines are "not a substitute for clinical judgment," the document reads, but represent an aggressive and immediate effort to stop bleeding and save lives.

Uncontrolled bleeding is one of the top causes of death on the battlefield, and roughly 85 percent of battlefield deaths occur within the first 30 minutes of wounding, research suggests. So time is of the essence. Some doctors who have served in military hospitals swear by these guidelines.

"Col. John Holcomb's guidelines are an incredibly aggressive and immediate effort to stop bleeding and to improve [blood flow to vital organs] and correct clotting defects," said Dr. Martin Schreiber, director of surgical critical care in the trauma and critical care section of Oregon Health & Science University in Portland, Ore.

Schreiber has used rF7a in Iraq as a doctor in the Army reserves.

Aggressive and immediate treatment are undoubtedly necessary, but is it safe to give rF7a as part of that treatment?

Doctors don't have the data to defend their work, but they can say what they have seen on the front lines. Holcomb's practice guidelines have led to "the best outcomes that have ever been seen in the history of warfare in terms of mortality," Schreiber said.

"I don't think you'll find anyone [who has served in a combat support hospital] who doesn't believe that the methodology doesn't save lives," Lucenti said.

But doctors cannot prove that rF7a is effective or safe for these wounded soldiers. There is no data to support any lifesaving effects, even though the military has been using the drug for years.

Holcomb insists, the military is doing its best to collect the information that its doctors have been trained to collect.

Right now, military patient records document roughly 300 U.S. soldiers who got rF7a as part of their trauma treatment at a military hospital, according to Cordts. Pharmacy records indicate that 600 patients total -- which includes U.S. soldiers and Iraqi citizens -- got the drug. As the military continues to review its patient and pharmacy databases, these numbers are expected to increase, Cordts said. "It's a massive amount of data to sort through," he said.

At this point, though, the Army cannot confirm whether those soldiers who were given rF7a lived or died once they left the immediate care of that support hospital.

From the rough numbers available we don't know who lived, who died, whose bleeding stopped, whose did not, or who went on to die of another cause that may or may not have been related to the drug.

"The military went about [using this drug] in completely the wrong way," 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.

"I don't believe that they don't have the capability to answer these questions. If you can't come to a conclusion, how do you come to the conclusion that it's safe?"

The military says that it has sharpened its focus on rF7a since the press and public began to question it.

"We've been tracking patient outcomes as best we can," Holcomb said. "But we're in a setting where patients are moving across continents in the span of days. The data moves quickly."

"It is hard to collect data in the middle of the war, because people are focused on saving people's lives," said Thomas Scalea, physician-in-chief at the Shock Trauma Center at the University of Maryland in Baltimore.

The realities of wartime and technological resources make it difficult for the military to maintain a comprehensive database, Holcomb said.

"It's not an excuse, it's just a fact," he said.

Battlefield Use Could Lead to Discovery

While use of rF7a presents a potential and potentially very serious risk to military patients, the off-label use of the drug could kick off a major medical advance.

Historically, the U.S. military has been responsible for several major medical advances.

"There is a whole history of war being a spur towards new medical innovations" said Bradford Kirkman-Liff, professor of health policy and technology at Arizona State University

"Radiology got first used in WWI to find bullets in wounded soldiers, and WWII led to mass production of penicillin, dialysis in the Korean War was used to treat Korean hemorrhagic fever," Kirkman-Liff said.

The military's use of rF7a in our current war may be consistent with this history.

"Like in any war, the methods are untested. They figure out what works and what doesn't on the fly, under critical conditions," said Dr. James Adams, chair of the department of emergency medicine at Northwestern University's Feinberg School of Medicine in Chicago. "Any danger will be one of the lessons, if the records are kept."

As of now, the military's records cannot tell us whether rF7a has been a miracle -- or a mistake.

On the Home Front

These questions don't exist only on the battlefield. Civilian doctors also use rF7a off-label, in trauma rooms to stop uncontrolled bleeding.

The drug is used differently on U.S. soil -- not as part of a first-line treatment, but as a last resort therapy. The drug purportedly works the same way -- for better or for worse -- in both arenas.

Some doctors swear that rF7a works miracles, but none deny its potential risks.

"The risk of dying [from uncontrolled bleeding] is extremely high and in our anecdotal experience -- which can be wrong -- the effect of rF7a is in some cases dramatic," said Dr. Demetrios Demetriades, director of trauma and surgical critical care at the University of Southern California in Los Angeles.

"We believe that rF7a played an important role, but nobody can prove that this is the case," Demetriades said.

Civilian hospitals suffer from the same problem as the military -- a lack of data that supports the use of rF7a. Federal regulations present real hurdles that make it difficult for doctors to get data, experts say. The drug is used rarely, because it's safety is so uncertain. So data is only dripping in case by case.

"No center or doctor uses it enough to note the complications. It would take many years for even a group of busy trauma centers to get enough data," said Dr. James Adams, chair of the department of emergency medicine at Northwestern's Feinberg School of Medicine.

"The regulations are extensive. Informed consent is a problem. Randomization is ethically unsettling, and funding is tricky," Adams said.

The lack of data makes the use of rF7a controversial, and some doctors say that controversy should be enough to persuade doctors not to use it.

"It is not that we just don't know what the right thing to do is, but I would say that we do know that when you use the drug outside of its approved uses it is accompanied by these [side effects] which can be fatal," said Dr. Walter Dzik, co-director of blood transfusion service at Massachusetts General Hospital in Boston.

"And so the use of the drug should be done in a way that protects patient's rights and welfare," Dzik said.

The Final Call a Judgment Call

But sometimes, there is no alternative to rF7a.

When a young child or soldier arrives in the emergency room, bleeding uncontrollably, surgeons can attempt to revive the patient with standard methods, or they can use a drug that could stop the bleeding within seconds, but isn't proven to be safe.

It is hard to know how dire a situation needs to be before it reaches a point no return -- when a last resort is the only hope.

Most doctors agree, in the absence of evidence, that rF7a is a drug that should not be given to every trauma patient. But the military guidelines that call for rF7a list specific criteria that a physician should look for before administering the drug -- but these guidelines do not trump a clinician's own judgment.

The physicians who spoke to ABC News about rF7a were all unwilling to second-guess the judgment of clinicians on the front lines. But most will say that this not a proven treatment, and there are risks to using the drug.

The resounding theme is the need for answers. Perhaps the military expects that both soldiers and civilians will want answers, as Aledort said.

"If it were my son and he was given this drug and he died later but that drug was being used under clinical study, I could know he died for a reason. Because he was part of a discovery," Aledort said.

"But if there were no answers, how could you look back and say rF7a did any good to anyone -- when you can't even say what it did to our soldiers?"

Until those answers are available, both military and civilian surgeons will continue to do the best they can with the information and medications available.