Does Erythropoietin monotherapy reduce mortality or moderate/severe disability in neonates with hypoxic ischaemic encephalopathy?

Erythropoietin (EPO) works by a number of mechanisms that gives it neuroprotective properties including decreasing neuronal apoptosis in the acute phase and enhancing angiogenesis and neurogenesis for long-term brain healing (1). Malla et al. (2) demonstrate improved neurologic outcomes in patients treated with EPO monotherapy vs placebo when treating moderate or severe hypoxic ischaemic encephalopathy (HIE). A study carried out in China by Zhu et al. (3) comparing EPO vs placebo, also without adjunctive therapeutic hypothermia (TH), showed similar results. Importantly, these studies showed a significant improvement in neurologic outcome in patients with moderate but not severe encephalopathy. There was also no difference in mortality between the placebo and EPO groups. This differs from trials with TH, the current standard of care inmost resource-rich areas, which show a similar reduction in combined mortality and morbidity, but also demonstrate a reduction in mortality [RR–0.75 (95% CI: 0.64, 0.88) [Table 1.2, reference (4)] and disability [RR–0.77 (95% CI: 0.63, 0.94) [Table 1.3, reference (4)], when stratified by moderate or severe encephalopathy (data not shown) (4). These differences could be attributed to the larger sample size of patients in the Cochrane review (4) compared to the singlecenter study (2) and are certainly reflected in the forest plots when looking at individual trials (4). In settings where TH is widely available, there is significant interest in the potential benefits of EPO as an adjunct therapy to TH. A phase I trial by Wu et al. (5) showed that a presumably effective dosing regimen of EPO could be safely given to neonates undergoing TH for HIE. In a phase II trial, Wu et al. (6) showed that infants treated with EPO as an adjunct to TH had less MRI brain injury and improved motor outcomes at 1 year of age. Currently, there are three phase III clinical trials underway (HEAL, PAEAN and Neurepo) comparing mortality and neurodevelopmental disability in term infants with HIE treated with EPO+ TH vs TH alone (7). These may reaffirm the safety of EPO as adjunct therapy to TH and substantiate evidence that it improves neurologic outcome. The number needed to treat (NNT) to prevent the composite measure of death or moderate or severe disability in this EPO monotherapy study was four (2), which is lower than most trials using TH alone, with an NNT of 7–9 (1); however, the number of patients studied to date is far fewer. There has never been a head to head trial comparing EPO monotherapy vs TH. Given the findings of Malla et al. (2), is it an investigation worth considering given the resource intensity associated with TH compared to EPO monotherapy? Perhaps more importantly, would this ever be ethically feasible given the lack of clinical equipoise for the proven effectiveness of TH – although TH as compared to placebo has not been studied in the developing world either. Therefore, if the addition of EPO as an adjunct to TH in the current phase three trials fails to show a benefit, there may be an opportunity to ask this question again. The more challenging issue will be if adjunct EPO therapy does show incremental benefit compared to placebo, does that close the door on a head to head EPO vs TH? The use of simulation models may help to tease out some of the incremental cost-benefit challenges and potentially lay groundwork for a head to head trial. Careful consideration, however, must be given to the benefits of TH beyond neuroprotection that EPO may not offer (i.e. cardiovascular, gastrointestinal system, etc.).