Is rescue based treatment or early conservative treatment superior in managing patent ductus arteriosus?

Abstract

Commentary on: Clyman RI, Liebowitz M, Kaempf J, Erdeve O, Bulbul A, Håkansson S, Lindqvist J, Farooqi A, Katheria A, Sauberan J, Singh J, Nelson K, Wickremasinghe A, Dong L, Hassinger DC, Aucott SW, Hayashi M, Heuchan AM, Carey WA, Derrick M, Fernandez E, Sankar M, Leone T, Perez J, Serize A, the PDA-TOLERATE (PDA: TO LEave it alone or Respond And Treat Early) Trial Investigators. PDA-TOLERATE trial: an exploratory randomized controlled trial of treatment of moderate-to-large patent ductus arteriosus at one week of age. J Pediatr 2018; 205: 41–48.e6. PMID: 30340932. Numerous poor outcomes in premature neonates are attributed to the persistent left-to-right shunt of a PDA, such as pulmonary haemorrhage, bronchopulmonary dysplasia and death. There is also concern that PDAs cause ‘systemic steal’, leading to intraventricular haemorrhage (IVH), hypotension and delay of time to full feeds 1, 2. The PDA is particularly problematic in the extremely premature neonate: Clyman et al. 3 showed spontaneous closure at seven days of life in 98% of those infants born at ≥30 weeks compared to just 13% of infants born at 24 weeks. No trial, however, has definitively shown reduced incidence of BPD or death with either prophylactic indomethacin or closure of the PDA regardless of timing 4. Thus, optimal management of the PDA in premature infants has long been a source of controversy among neonatologists. According to the authors, this study, which they describe as a pilot exploratory trial, had two goals – to evaluate whether there is a difference between presumptive and rescue-based treatment of the PDA on ligation and presence of PDA at discharge, and to obtain data on several secondary outcomes to appropriately power future investigations. This trial addressed the current knowledge gap by focusing solely on infants with moderate-to-large PDAs present after the first week of life and evaluating PDA exposure to assess for long-term outcomes throughout hospitalisation. There was no statistically significant difference, however, in the primary outcome or in many of the pre-specified secondary outcomes. The authors note many limitations of their trial, which can make this paper difficult for clinicians to generalise to their populations. The primary outcome is difficult to apply to clinical practice, as most clinicians are less interested in the presence of PDA as they are in preventing its long-term consequences. The small size of the study and high rate (almost 50%) of rescue treatment in the CT arm could have contributed to the lack of difference in the outcomes of the two groups. Further, the multiple comparisons required for the statistical analysis of groups and subgroups impedes our ability to draw conclusions from the appearance of statistical significance. What the results of this study do suggest is that clinicians should not feel obligated to automatically treat every PDA. Based on the data presented, a reasonable strategy is to follow the infant's clinical status, treating when necessary. With this strategy, about 50% of infants with a persistent PDA may avoid exposure to the harms of NSAIDs and ligation by the time of discharge. This study also highlights the need for larger trials to assess the long-term consequences of prolonged PDA exposure in lower gestational age infants. This study also helps inform future trials about specific sub-populations of infants to include, and about required sample sizes. https://ebneo.org/2019/04/pda-tolerate-trial/ None. This study was funded by grants from the Gerber Foundation, US Public Health Service, National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences, and National Institutes of Health and a gift from the Jamie and Bobby Gates Foundation.