The CRASH trial has screeched to an emergency landing, with accrual prematurely halted because of an unexpected – and alarming – excess of deaths in head injury patients treated with corticosteroids, compared with those given placebo. (CRASH stands for Corticosteroid Randomization After Significant Head injury.)
The results were published in the Lancet (2004;364:1321–1326).
Dr. Mark P. Cilo: “Overall, the use of brain steroids after brain injury, which has been diminishing over the past decade, will be reduced even further.”
The significant 18-percent relative increase in the two-week mortality rate associated with steroids should help put an end to the already dwindling use for traumatic brain injury in the US, most experts contacted by Neurology Today agreed.
“The [American Association of Neurological Surgeons/Brain Trauma Foundation] recommendations state there is no role for corticosteroids in the treatment of head injury, and the study supports that,” said Barry D. Jordan, MD, MPH, Director of the Brain Injury Program at Burke Rehabilitation Hospital in White Plains, NY.
“Overall, the use of brain steroids after brain injury, which has been diminishing over the past decade, will be reduced even further,” said Mark P. Cilo, MD, Founder of the Brain Injury Treatment Program at Craig Hospital in Englewood, CO, and Assistant Clinical Professor in the Physical Medicine and Rehabilitation Department at the University of Colorado Health Sciences Center in Denver. “This is a very important study.”
But until the six-month morbidity data are published, it's too soon to conclude that corticosteroids are contraindicated in all patients, he said. If the drugs reduce disability, there may prove to be subgroups of patients, such as those with severe injury or evacuated hematomas, for whom the benefits outweigh the mortality risk, he said.
Traumatic brain injury is common, resulting in about one million visits to US emergency rooms each year, according to the Centers for Disease Control and Prevention. About 280,000 Americans are admitted to hospitals for severe injuries, and 50,000 of them die. Worldwide, the figures are even more staggering, with some three million people dying of trauma every year.
UNCERTAIN EVIDENCE FOR CORTICOSTEROIDS
Post-traumatic inflammatory changes are thought to contribute to neuronal degeneration, and corticosteroids have been used to treat head injury for about 50 years, said Ian Roberts, MD, PhD, Clinical Coordinator of the CRASH trial and a Professor of Epidemiology at the London School of Hygiene and Tropical Medicine in the United Kingdom. A survey of intensive-care management of patients with a head injury in the US, published in 1995, indicated that corticosteroids were used in 64 percent of trauma centers (Crit Care Med 1995;23:560–567).
Nevertheless, “the evidence for the use of these drugs has been uncertain,” he said. “Previous randomized clinical trials were small, and a 1997 systematic review (BMJ 1997;314:1855–59) found that there could be anywhere from 6 percent fewer deaths to 3 percent more deaths associated with the use of corticosteroids.”
Around that time, the American Association of Neurological Surgeons and the Brain Trauma Foundation convened a panel of experts to sort through the evidence and issue guidelines for the management of severe brain injury in adults with a Glasgow coma scale score of 3 to 8. Citing “a high degree of clinical certainty,” the panel concluded that “the use of steroids is not recommended for improving outcome or reducing intracranial pressure in patients with severe head injury” (J Neurotrauma 2000;17:451–627).
In arriving at that recommendation, the panel considered the results of the meta-analysis “as well as four other studies of various steroids, all of which showed no benefit,” said James P. Kelly, MD, Visiting Professor in the Department of Neurosurgery at the University of Colorado School of Medicine in Denver.
Dr. James P. Kelly: “One trial showed that treatment with methylprednisolone significantly increased recovery rates in patients with acute spinal cord injuries. The logical extension was to try it in traumatic brain injury.”
CRASH TRIAL RESULTS
“But one trial showed that treatment with methylprednisolone significantly increased recovery rates in patients with acute spinal cord injuries. The logical extension was to try it in traumatic brain injury,” said Dr. Kelly, a nonvoting panelist who reviewed the guidelines on behalf of the AAN.
This is just what the CRASH investigators did. “We designed a huge, multicenter international study to find the answer,” Dr. Roberts said. The study, which was to recruit 20,000 patients, was stopped prematurely in May 2004, after the data monitoring committee disclosed the unmasked results to the steering committee.
“It was a huge surprise,” Dr. Roberts said. “A treatment that had been used for more than 50 years did not decrease mortality, but actually increased it by an absolute 3 percent.”
At the time the study was stopped, 10,008 adults from 239 hospitals in 49 countries with head injury and a Glasgow coma scale score of 14 or less within eight hours of injury had been randomly allocated to a 48-hour infusion of methylprednisolone or placebo.
As reported in Lancet, the data showed that 21.1 percent of patients given corticosteroids died within the next two weeks, compared with 17.9 percent of those given placebo, corresponding to a relative risk of 1.18.
Dr. Barry D. Jordan: “The [American Association of Neurological Surgeons/Brain Trauma Foundation] recommendations state there is no role for corticosteroids in the treatment of head injury, and the study supports that.”
Among patients with severe brain injury, as measured by a Glasgow coma scale score of 3 to 8, 39.8 percent of those taking steroids died, compared with 34.8 percent of those on placebo. The apparent increase in mortality associated with steroid use did not differ significantly in patients with severe injuries and those with mild or moderate injures or in other prespecified subgroups in which patients were classified according to time since injury or CT diagnosis, Dr. Roberts said.
ANALYSIS OF TRENDS
But certain trends did emerge, Dr. Cilo said. Coupled with the fact that six-month follow-up disability data have yet to be published, which means the final answer still isn't in, he said. “We know the answer in terms of mortality – that is, that mortality alone warrants stopping therapy. But if the morbidity data are clearly positive, we might see a return to the debate.”
When looked at by CT diagnosis, for example, patients with evacuated hematomas fared the best, with steroid use associated with a slight, although non-significant, decreased risk of death. “This is interesting because steroids are used to reduce swelling around hematomas,” Dr. Cilo said. “The presence of a hematoma might weight toward still using steroids if the morbidity data are positive.”
When looked at by severity of injury, corticosteroids increased the risk of death in all three subgroups, although the worst impact was observed in those with moderate injury, as indicated by a Glasgow coma score of 9 to 12.
But even among those with severe head injury, any positive morbidity data should be considered against negative mortality data, Dr. Cilo said. “Severe patients have such significant morbidity that if the patient will be slightly less impaired, a slightly higher risk of death is a tradeoff that should be discussed on a case-by-case basis,” he said.
Dr. Ian Roberts: “The CRASH trial has shown that we can enroll trauma patients into clinical trials, even in the emergency setting. Studies of other treatments for traumatic brain injury, including barbiturates, hypothermia, and mannitol, are clearly needed.”
“The Glasgow coma scale is broad. Neurosurgeons [developing treatment guidelines] might not experience the negative impact that some severe injuries have on patients and their families that we see in rehab.”
UNKNOWN: WHY STEROIDS INCREASE DEATH
Still unanswered is the question of why steroids increase death, Dr. Cilo added. “The researchers saw no evidence of a large risk of infectious complications or gastrointestinal bleeding from corticosteroid treatment, the major mechanisms one would expect to increase mortality. This implies there is some neurological adverse effect of steroids on the newly injured brain that we still don't know about,” he said.
But Dr. Roberts downplayed the importance of understanding mechanisms in arriving at clinical recommendations. “Making sense biologically is not good enough. With enough creative imagination, you can make anything make sense.”
What matters are large-scale randomized trials, he said, adding that many other treatments of uncertain effectiveness for head injury are also in widespread use.
“The CRASH trial has shown that we can enroll trauma patients into clinical trials, even in the emergency setting,” Dr. Roberts said. “Studies of other treatments for traumatic brain injury, including barbiturates, hypothermia, and mannitol, are clearly needed.”
ARTICLE IN BRIEF
- ✓ A new study reported that the treatment of traumatic brain injury with corticosteroids increased mortality risk by 3 percent.