Cause and timing of death and sub-group differential effects of erythropoietin in the EPO-TBI study.

The EPO-TBI study randomised 606 patients with moderate or severe traumatic brain injury (TBI) to be treated with weekly epoetin alfa (EPO) or placebo. Six-month mortality was lower in EPO treated patients in an analysis adjusting for TBI severity. Knowledge of possible differential effects by TBI injury subtype and acute neurosurgical treatment as well as timing and cause of death (COD) will facilitate the design of future interventional TBI trials. We defined COD as cerebral (brain death, cerebral death with withdrawal or death during maximal care) and non-cerebral (death following withdrawal or during maximal care due to a non-cerebral cause). The study included 305 patients treated with EPO and 297 with placebo, with COD recorded in 77 (99%) out of 78 non-survivors. Median time to death in patients dying of cerebral COD was 8 days (IQR 5-16) compared to 29 days (IQR 7-56) (p=0.01) with non-cerebral COD. When assessing subgroups by admission computed tomography scan injury findings, we found no significant differential effects of EPO compared to placebo. However, EPO appeared more effective in patients with an injury type not requiring a neurosurgical operation prior to ICU admission (OR 0.29, 95% confidence interval 0.14-0.61, p=0.001, p for interaction = 0.003) and in this sub-group, fewer patients died of cerebral causes in in the EPO compared to placebo group (5% compared to 14%, p=0.03). In conclusion, most TBI deaths were due to cerebral causesthat occurred during the first two weeks, and were related to withdrawal of care. EPO appeared to specifically reduce cerebral deaths in the important subgroup of patients with a diffuse type of injury not requiring a neurosurgical intervention prior to randomisation.