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Erythropoiesis and the mystery of an unexplained survival benefit.

Erythropoiesis-stimulating agents (ESA) have a tried history and proven indication in anemic patients with renal failure. Their effectiveness in other diseases is under constant investigation, but the results are mixed. The 2007 prospective randomized New England Journal of Medicine study by Corwin et al in critically ill patients served to muddy rather than clarify the picture. The primary outcome (blood transfusion) was not improved, but one of the secondary outcomes (mortality) “tended to be lower” among patients randomized to receive epoetin alfa. This effect was even more powerful among trauma patients. The secondary outcome improvement was gained at the expense of more thrombotic complications. To explain these results the authors postulated some poorly understood interactions of ESA with the post-traumatic inflammatory cascade. Thus, for obvious reasons the drug has been used sparingly in surgical and trauma patients. The current report by Talving et al, from the Los Angeles County and University of Southern California Medical Center trauma group confirms the rule of infrequent use, as only 5% of their critically injured patients received an ESA. It is unknown, whether the use was based on an expectation of improving the hemoglobin (not supported by the Corwin trial) or improving mortality (as the Corwin trial suggests). The group—always at the forefront of innovation and restless exploration—attempted to retrospectively define a subpopulation that could benefit from ESAs, ie, severe head injury patients. The investigators found in a 1:2 ESA:no-ESA matched-pairs analysis that the survival rate was higher among ESA patients. The matching was done carefully and by many variables. The statistical analysis is robust and commensurate with the high research standards of the group. However, along the same confusing lines as the Corwin trial, the results serve more to provoke questions than provide answers.