The effect of recombinant erythropoietin on long-term outcome after moderate-to-severe traumatic brain injury

Abstract

Purpose: Recombinant erythropoietin (EPO) administered for traumatic brain injury (TBI) may increase short-term survival, but the long-term effect is unknown.

Methods: We conducted a pre-planned long-term follow-up of patients in the multicentre erythropoietin in TBI trial (2010-2015). We invited survivors to follow-up and evaluated survival and functional outcome with the Glasgow Outcome Scale-Extended (GOSE) (categories 5-8 = good outcome), and secondly, with good outcome determined relative to baseline function (sliding scale). We used survival analysis to assess time to death and absolute risk differences (ARD) to assess favorable outcomes. We categorized TBI severity with the International Mission for Prognosis and Analysis of Clinical Trials in TBI model. Heterogeneity of treatment effects were assessed with interaction p-values based on the following a priori defined subgroups, the severity of TBI, and the presence of an intracranial mass lesion and multi-trauma in addition to TBI.

Results: Of 603 patients in the original trial, 487 patients had survival data; 356 were included in the follow-up at a median of 6 years from injury. There was no difference between treatment groups for patient survival [EPO vs placebo hazard ratio (HR) (95% confidence interval (CI) 0.73 (0.47-1.14) p = 0.17]. Good outcome rates were 110/175 (63%) in the EPO group vs 100/181 (55%) in the placebo group (ARD 8%, 95% CI [Formula: see text] 3 to 18%, p = 0.14). When good outcome was determined relative to baseline risk, the EPO groups had better GOSE (sliding scale ARD 12%, 95% CI 2-22%, p = 0.02). When considering long-term patient survival, there was no evidence for heterogeneity of treatment effect (HTE) according to severity of TBI (p = 0.85), presence of an intracranial mass lesion (p = 0.48), or whether the patient had multi-trauma in addition to TBI (p = 0.08). Similarly, no evidence of treatment heterogeneity was seen for the effect of EPO on functional outcome.

Conclusion: EPO neither decreased overall long-term mortality nor improved functional outcome in moderate or severe TBI patients treated in the intensive care unit (ICU). The limited sample size makes it difficult to make final conclusions about the use of EPO in TBI.

Keywords: Erythropoietin; Neurological outcome; Traumatic brain injury.

Fig. 1

Flow chart of included patients. GOS Glasgow Outcome Scale-Extended, QOL quality of life

Fig. 2

Long-term survival in patients with moderate or severe traumatic brain injury and treated with erythropoietin (EPO) or placebo [hazard ratio EPO vs placebo 0.73, 95% confidence interval 0.47–1.14)

Fig. 3

Survival analysis shown as hazard ratios and 95% confidence intervals in all patients included in the EPO-TBI trial. AIS abbreviated injury scale, CI confidence interval, HR hazard ratio, ISS injury severity score, TBI traumatic brain injury

Fig. 4

Distribution of neurological long-term outcome by the Glasgow Outcome Scale-Extended in those 356 patients treated with erythropoietin or placebo with complete data on functional outcome. EPO erythropoietin, GOSE Glasgow Outcome Scale-Extended. The median time to GOSE assessment was 6.4 years (IQR 5.6–7.1) in the EPO group and 6.2 (IQR 5.3–7.2) a non-significant difference (p = 0.31)