Erythropoietin fails to lower death in neonates with neurologic condition
High-dose erythropoietin failed to lower the risk for death among newborns undergoing therapeutic hypothermia for neonatal hypoxic ischemic encephalopathy, according to study findings published in The New England Journal of Medicine.
The phase 3 High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial also demonstrated that erythropoietin was linked to a higher rate of serious adverse events compared with placebo.
The results contradicted findings from smaller preclinical studies that supported the use of erythropoietin, but they supported other studies that found it was not neuroprotective.
“Neonatal hypoxic-ischemic encephalopathy refers to neurologic dysfunction resulting from a reduction of oxygen and blood flow to a fetus’s brain near the time of birth and is an important cause of brain injury in term and near-term infants,” the authors of the new study wrote.
They enrolled 501 infants in a double-blind, randomized, placebo-controlled trial and randomly assigned them between Jan. 25, 2017, through Oct. 9, 2019, to receive either erythropoietin (1,000 U per kilogram of body weight) or placebo, in conjunction with standard therapeutic hypothermia.
The infants were from 23 U.S. hospitals and were born at 36 weeks or more of gestation with moderate or severe hypoxic–ischemic encephalopathy. Among the 500 infants included in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received a placebo.
Among participants included in the efficacy analysis, death or neurodevelopmental impairment at 22 to 36 months of age — the primary outcome — occurred in 126 of 240 children (52.5%) in the erythropoietin group and in 110 of 222 children (49.5%) in the placebo group, for a RR of 1.03 (95% CI, 0.86-1.24).
Infants in the treatment group experienced a higher mean number of serious adverse events than infants the placebo group — 0.86 vs. 0.67 per child, for a RR of 1.26 (95% CI, 1.01 to 1.57).
“We found that multiple high doses of erythropoietin given with therapeutic hypothermia to term and near-term newborn infants with moderate or severe hypoxic-ischemic encephalopathy did not significantly affect the incidence of death or neurodevelopmental impairment at 2 to 3 years of age,” they wrote. “Furthermore, infants who received erythropoietin were more likely to have at least one serious adverse event and had a greater number of serious adverse events than those who received placebo.”
Perspective
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Neonatal encephalopathy from acute perinatal hypoxia-ischemia is one of the major neurological conditions that can affect a baby at birth, cause death and have long-term consequences on neurodevelopment. Unfortunately, about 40% of newborns still have death or disability from moderate to severe neonatal encephalopathy following the standard-of-care therapy for therapeutic hypothermia. Thus, there is a need to find additional treatments to reduce the number of infants still facing lifetime challenges.
Erythropoietin was an exciting candidate to lower the burden of death and long-term developmental disabilities based on preclinical, phase 1 and phase 2 studies. The large international community of providers involved in caring for babies with neonatal encephalopathy have been eagerly awaiting the results of this important clinical trial. Many were hopeful that erythropoietin could be offered as an additional neuroprotectant to help their patients.
This multicenter, double-blind, randomized, placebo-controlled phase 3 trial published in The New England Journal of Medicine and led by Dr. Yvonne Wu, Dr. Sunny Juul, and the HEAL consortium enrolled 501 infants to determine if the combination of erythropoietin in addition to therapeutic hypothermia lowered the rate of death and disability for infants with moderate to severe neonatal encephalopathy. The study was a beautifully designed massive undertaking and enrolled more babies than any of the prior three human therapeutic hypothermia trials. However, the study did not find a benefit of erythropoietin in addition to the therapeutic hypothermia and found a higher rate of adverse events among infants who received erythropoietin.
The findings of this study, demonstrate how important it is to embark on well-designed clinical trials to understand safety and efficacy before making significant changes in clinical protocols. Each step of the evolution of a new therapy through the phases of a clinical trial has an important role in ensuring safety and improved outcomes for patients. I congratulate the investigators on this very important study to help us best care for babies with neonatal encephalopathy.Collapse
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