Erythropoietin in traumatic brain injury (EPO-TBI): a double-blind randomised controlled trial.

BACKGROUND: Erythropoietin might have neurocytoprotective effects. In this trial, we studied its effect on neurological recovery, mortality, and venous thrombotic events in patients with traumatic brain injury. METHODS: Erythropoietin in Traumatic Brain Injury (EPO-TBI) was a double-blind, placebo-controlled trial undertaken in 29 centres (all university-affiliated teaching hospitals) in seven countries (Australia, New Zealand, France, Germany, Finland, Ireland, and Saudi Arabia). Within 24 h of brain injury, 606 patients were randomly assigned by a concealed web-based computer-generated randomisation schedule to erythropoietin (40,000 units subcutaneously) or placebo (0·9% sodium chloride subcutaneously) once per week for a maximum of three doses. Randomisation was stratified by severity of traumatic brain injury (moderate vs severe) and participating site. With the exception of designated site pharmacists, the site dosing nurses at all sites, and the pharmacists at the central pharmacy in France, all study personnel, patients, and patients' relatives were masked to treatment assignment. The primary outcome, assessed at 6 months by modified intention-to-treat analysis, was improvement in the patients' neurological status, summarised as a reduction in the proportion of patients with an Extended Glasgow Outcome Scale (GOS-E) of 1-4 (death, vegetative state, and severe disability). Two equally spaced preplanned interim analyses were done (after 202 and 404 participants were enrolled). This study is registered with ClinicalTrials.gov, number NCT00987454. FINDINGS: Between May 3, 2010, and Nov 1, 2014, 606 patients were enrolled and randomly assigned to erythropoietin (n=308) or placebo (n=298). Ten of these patients (six in the erythropoietin group and four in the placebo group) were lost to follow up at 6 months; therefore, data for the primary outcome analysis was available for 596 patients (302 in the erythropoietin group and 294 in the placebo group). Compared with placebo, erythropoietin did not reduce the proportion of patients with a GOS-E level of 1-4 (134 [44%] of 302 patients in the erythropoietin group vs 132 [45%] of 294 in the placebo group; relative risk [RR] 0·99 [95% CI 0·83-1·18], p=0·90). In terms of safety, erythropoietin did not significantly affect 6-month mortality versus placebo (32 [11%] of 305 patients had died at 6 months in the erythropoietin group vs 46 [16%] of 297 [16%] in the placebo group; RR 0·68 [95% CI 0·44-1·03], p=0·07) or increase the occurrence of deep venous thrombosis of the lower limbs (48 [16%] of 305 vs 54 [18%] of 298; RR 0·87 [95% CI 0·61-1·24], p=0·44). INTERPRETATION: Following moderate or severe traumatic brain injury, erythropoietin did not reduce the number of patients with severe neurological dysfunction (GOS-E level 1-4) or increase the incidence of deep venous thrombosis of the lower limbs. The effect of erythropoietin on mortality remains uncertain. FUNDING: The National Health and Medical Research Council and the Transport Accident Commission.

Cost-Effectiveness of Erythropoietin in Traumatic Brain Injury: A Multinational Trial-Based Economic Analysis.

The EPO-TBI multi-national randomized controlled trial found that erythropoietin (EPO), when compared to placebo, did not affect 6-month neurological outcome, but reduced illness severity-adjusted mortality in patients with traumatic brain injury (TBI), making the cost-effectiveness of EPO in TBI uncertain. The current study uses patient-level data from the EPO-TBI trial to evaluate the cost-effectiveness of EPO in patients with moderate or severe TBI from the healthcare payers' perspective. We addressed the issue of transferability in multi-national trials by estimating costs and effects for specific geographical regions of the study (Australia/New Zealand, Europe, and Saudi Arabia). Unadjusted mean quality-adjusted life-years (QALYs; 95% confidence interval [CI]) at 6 months were 0.027 (0.020-0.034; p < 0.001) higher in the EPO group, with an adjusted QALY increment of 0.014 (0.000-0.028; p = 0.04). Mean unadjusted costs (95% CI) were $US5668 (-9191 to -2144; p = 0.002) lower in the treatment group; controlling for baseline IMPACT-TBI score and regional heterogeneity reduced this difference to $2377 (-12,446 to 7693; p = 0.64). For a willingness-to-pay threshold of $US50,000 per QALY, 71.8% of replications were considered cost-effective. Therefore, we did not find evidence that EPO was significantly cost-effective in the treatment of moderate or severe TBI at 6-month follow-up.

Deep vein thrombosis and pulmonary embolus in patients with traumatic brain injury: a prospective observational study.

BACKGROUND: Intensive care patients with traumatic brain injury (TBI) are at high risk of developing deep vein thrombosis (DVT). A high rate of DVT was reported before routine thromboprophylaxis, but the current DVT rate in TBI patients receiving best-practice mechanical and pharmacological prophylaxis is unknown. OBJECTIVES: To determine the prevalence of DVT among TBI patients. DESIGN, PARTICIPANTS AND SETTING: A prospective observational pilot study of adult patients admitted to the intensive care unit of a level 1 trauma centre within 72 hours of sustaining a TBI (Glasgow Coma Scale score _14). MAIN OUTCOME MEASURES: Rate of DVT determined using twice-weekly compression ultrasound; rate of pulmonary embolism (PE) and length of stay. RESULTS: 36 patients (28 men; mean age, 40.3 years) were included. Six had moderate and 21 had severe TBI. Two patients (6%) developed a DVT and two patients (6%) developed a PE. The proximal leg DVT rate was 3%, but the overall venous thromboembolism rate was 11% (4 patients). CONCLUSIONS: Mechanical and pharmacological prophylaxis appeared to be effective. The incidence of clinically identified PE is of concern and suggests that thromboembolic sources other than large leg veins may not be being adequately controlled by modern thromboprophylaxis regimens.