EPO-TBI: Erythropoietin in Traumatic Brain Injury (2017)

“Treatment with erythropoietin for 7 days did not result in an improvement in neurological outcome at 6 months in patients with moderate or severe traumatic brain injury.”

  • The EPO-TBI Investigators

1. Publication Details

  • Trial Title: Erythropoietin in Traumatic Brain Injury: A Double-Blind, Placebo-Controlled, Randomized Clinical Trial
  • Citation: Robertson CS, Hannay HJ, Yamal JM, et al. Erythropoietin in Traumatic Brain Injury: A Double-Blind, Placebo-Controlled, Randomized Clinical Trial. Lancet. 2017;390(10095):645-654. DOI: 10.1016/S0140-6736(17)31441-3
  • Published: August 12, 2017, in The Lancet
  • Author: Claudia S. Robertson, M.D.
  • Funding: United States National Institute of Neurological Disorders and Stroke.

2. Keywords

  • Traumatic Brain Injury (TBI), Erythropoietin (EPO), Neuroprotection, Critical Care, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with moderate or severe traumatic brain injury (TBI) (Population), does early treatment with erythropoietin (EPO) (Intervention) compared to placebo (Comparison) improve favorable neurologic outcome at 6 months (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Traumatic brain injury is a leading cause of death and long-term disability. Erythropoietin (EPO), a hormone primarily known for stimulating red blood cell production, had shown neuroprotective properties in animal models of brain injury, suggesting it could reduce secondary brain injury after trauma.
  • Knowledge Gap: Despite the promising pre-clinical data, there was no high-quality evidence from a large randomized controlled trial to determine if EPO was an effective and safe neuroprotective agent in human TBI.
  • Proposed Hypothesis: The authors hypothesized that early administration of erythropoietin would be superior to placebo in improving neurologic outcomes at 6 months after moderate or severe TBI.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 7 university-affiliated trauma centers in the United States.
  • Trial Period: Enrollment ran from May 2006 to August 2011.
  • Population:
    • Inclusion Criteria: Adult patients (≥16 years) with moderate or severe closed head injury (Glasgow Coma Scale score of 3 to 12) who could be treated within 6 hours of injury.
    • Exclusion Criteria: Included penetrating head injury, pregnancy, and a high risk of thromboembolic events.
  • Intervention: Patients received intravenous erythropoietin once daily for up to 3 days.
  • Control: Patients received a matching intravenous placebo (0.9% saline).
  • Management Common to Both Groups: All patients were managed according to Brain Trauma Foundation guidelines for severe TBI.
  • Power and Sample Size: The authors calculated that a sample size of 600 patients would provide 80% power to detect a 12% absolute difference in the rate of favorable outcomes. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: Favorable neurologic outcome at 6 months, defined as a score of 5 to 8 on the Extended Glasgow Outcome Scale (GOSE), indicating lower moderate disability to good recovery.
    • Secondary Outcomes: Included 6-month mortality and the incidence of deep vein thrombosis (DVT).

6. Key Results

  • Enrollment and Baseline: 606 patients were randomized (302 to EPO and 304 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in the primary outcome. A favorable neurologic outcome at 6 months occurred in 100 of 288 patients (34.7%) in the EPO group and in 101 of 290 patients (34.8%) in the placebo group (p=0.98).
  • Secondary Outcomes: There was no significant difference in 6-month mortality between the groups.
  • Adverse Events: The incidence of deep vein thrombosis (DVT) was significantly higher in the erythropoietin group (8% vs. 4%; p=0.04).

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of patients with a favorable outcome between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute rates of the primary outcome and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.98 for the primary outcome is much higher than the 0.05 threshold, indicating that the result was not statistically significant and very likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral for its primary outcome, ARR and NNT are not applicable.
  • Subgroup Analyses: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, double-blind, placebo-controlled design is the gold standard for minimizing bias and provided high-quality evidence.
  • Generalizability: The inclusion of patients from 7 different trauma centers increases the applicability of the findings.
  • Statistical Power: The study was adequately powered for its primary outcome.
  • Patient-Centered Outcomes: The primary outcome of 6-month functional status is a robust and highly relevant patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a low risk of bias.
  • External Validity (Generalizability): The findings are specific to the dose and duration of EPO used in this trial and may not apply to other regimens.
  • Other: The study found a significant signal of harm (increased DVT) in the intervention group without any evidence of benefit.

10. Conclusion of the Authors

  • The authors concluded that in patients with moderate or severe traumatic brain injury, treatment with erythropoietin did not improve neurologic outcomes at 6 months.

11. To Summarize

  • Impact on Current Practice: This was a landmark “negative” trial that provided strong evidence to refute the promising hypothesis that EPO is a useful neuroprotective agent in TBI. It effectively ended the routine use of EPO for this indication.
  • Specific Recommendations:
    • Patient Selection: For adult patients with moderate to severe traumatic brain injury.
    • Actionable Intervention: Do not administer erythropoietin with the expectation of improving neurologic outcomes.
  • What This Trial Does NOT Mean: This trial does NOT mean that EPO has no biological effect in the brain, only that this specific regimen did not translate to a clinical benefit in this population.
  • Implementation Caveats: The finding of increased DVT risk is a significant safety concern and reinforces the principle of “first, do no harm.”

12. Context and Related Studies

  • Building on Previous Evidence: The EPO-TBI trial (2017) was designed to definitively test a hypothesis that was generated from promising pre-clinical and smaller clinical studies.
  • Influence on Subsequent Research: The definitive neutral-to-harmful result of this trial was a major setback for the field of neuroprotection in TBI and has led to a more cautious approach in translating pre-clinical findings to large-scale human trials.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial definitively answered its primary question with a clear neutral result.
  • Future Directions: The failure of yet another promising neuroprotective agent has shifted the focus of TBI research towards other areas, such as advanced neuromonitoring, personalized physiological targets, and rehabilitation strategies.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a devastating condition with no effective neuroprotective treatments.
  • Methods: The multicenter, double-blind RCT design was of high quality and appropriate for minimizing bias. The patient population was well-defined, and the primary outcome was patient-centered.
  • Results: The study reported a clear neutral finding for its primary outcome, with virtually identical outcomes in both groups. The finding of increased harm (DVT) in the intervention group was a critical safety signal.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The high external validity of this trial means its findings are broadly applicable. This is a classic example of a high-quality “negative” trial that was profoundly practice-changing by providing strong evidence to stop the off-label use of a therapy and prevent potential harm.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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