Neurological outcomes were not improved in patients with severe traumatic brain injuries (TBI) when they received erythropoietin (EPO) with transfusions to normalize blood hemoglobin levels, a randomized trial indicated.
The likelihood of Glasgow Outcome Scale scores rated as favorable at 6 months post-injury did not differ significantly between treatment groups in the placebo-controlled, 200-patient trial, according to Claudia S. Robertson, MD, of Baylor College of Medicine in Houston, and colleagues.
Moreover, adverse events were more common in patients treated to a hemoglobin target of 10 g/dL versus 7 g/dL, the researchers reported in the July 2 issue of the Journal of the American Medical Association.
As a result, Robertson and colleagues concluded that neither use of EPO nor treating to a 10-g/dL hemoglobin target was helpful, at least in terms of overall outcomes.
They noted that the results contradicted usual practice, since anemia is common in patients with severe TBI and clinicians have long used transfusions to maintain blood hemoglobin near 10 g/dL to ensure adequate brain oxygenation.
"This transfusion practice was expected to reduce neurological injury, particularly during the acute recovery period when the brain is most vulnerable to ischemic insults," Robertson and colleagues wrote. Also, an earlier study had found that erythropoiesis-stimulating agents cut mortality in TBI patients.
However, Steven M. Steinberg, MD, director of the trauma, critical care and burns division at Ohio State University, told MedPage Today in an email that, in his experience, 7-g/dL is most commonly used as the threshold for transfusing TBI patients.
"There are many studies in ICU patient populations that show that transfusing patients to hemoglobin levels greater than 7 is actually associated with worse outcomes," said Steinberg, who was not involved with the study.
The current results supported Steinberg's view.
Of the 200 patients enrolled in the trial, 102 patients were assigned to receive EPO and 98 to placebo. Patients in both groups were also randomized to the 7- or 10-g/dL hemoglobin targets, with packed red cell transfusions used in patients falling short of their assigned targets.
The first 74 patients received EPO at 500 IU/kg or placebo daily by infusion for 3 days and then weekly for an additional 2 weeks. At that point, the FDA raised concerns about the EPO dosing regimen because of results from a different study that suggested an increased mortality risk. Robertson and colleagues then eliminated the EPO and placebo infusions given on study days 2 and 3 for the remaining 126 patients.
The study's primary outcome measure was the Glasgow Outcome Scale, a five-level categorical measure that ranges from "dead" to "good recovery." Patients in the top two categories (the second being "moderate disability") were classed as having favorable outcomes; death or ratings of severe disability or vegetative state were defined as unfavorable.
Robertson and colleagues also used the 31-point Disability Rating Scale as a secondary outcome, and also looked at three safety outcomes -- death, major infections, and adult respiratory distress syndrome (ARDS).
Among 89 patients in the placebo group with 6-month Glasgow scores available, 38.2% (95% CI 28.1%-49.1%) achieved favorable outcomes, compared with 48.6% (95% CI 31.4%-66.0%) of the 35 receiving EPO under the initial dosing regimen and 29.8% (95% CI 18.4%-43.4%) of the 57 receiving the drug under the amended protocol.
Outcomes were slightly but nonsignificantly better for the patients treated to the 7-g/dL hemoglobin target than for those with the more conventional higher target. Favorable outcomes were achieved by 42.5% of those with the lower target versus 33.0% of those treated to 10 g/dL (P=0.28).
There was also a clear and significant benefit for the lower target in terms of thromboembolic events in a post hoc analysis: those with the 7-g/dL target had such events at a rate of 8.1%, compared with 21.8% among those treated to 10 g/dL (P=0.009).
For the three predefined safety outcomes, however, there were no significant differences either between EPO and placebo or between hemoglobin targets. But there was a strong trend toward higher rates of ARDS in patients treated to the 10 g/dL target versus the lower level (hazard ratio 1.79, P=0.08).
Although the study was a randomized, controlled trial, Robertson and colleagues noted several limitations. They suggested that the study may have been underpowered, because the trial had been designed to detect a large expected difference in outcomes between the two hemoglobin target groups. Also, it took 6 years to complete enrollment, and the trial was conducted at only two clinical sites, which might limit its generalizability.
Finally, the change in EPO dosing could have been an important factor in the results. Robertson and colleagues wrote that the initial 3-day loading dose has appeared more effective in some studies, but it was not used in 60% of the patients -- limiting the conclusions that could be drawn about EPO's efficacy, they suggested.
The study was funded by the National Institute of Neurological Disorders and Stroke (NINDS).
Study authors disclosed no relevant relationships except for other research grants from NINDS.
- Reviewed by F. Perry Wilson, MD, MSCE Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania
Journal of the American Medical AssociationSource Reference: Robertson C, et al "Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: A randomized clinical trial" JAMA 2014; 312: 36-47.