Comparison of Various Pharmacologic Agents in the Management of Hemodynamically Significant Patent Ductus Arteriosus in Preterm: A Network Meta-Analysis and Risk-Benefit Analysis

Abstract

Introduction: Various pharmacological treatments are available for preterm infants with patent ductus arteriosus (PDA), but their risks and benefits are controversial. This study aimed to identify the best treatment for PDA using network meta-analysis (NMA) and risk-benefit assessment (RBA).

Methods: Relevant randomized controlled trials (RCTs) were identified from MEDLINE, Scopus, and the Cochrane Library. RCTs were eligible if they were studied for preterm or low birth weight infants with presymptomatic PDA and hemodynamically significant PDA (hsPDA). The outcomes were PDA closure for a benefit and the composite risk outcome of adverse effects (AEs) for risk. An NMA was used to estimate the treatment effects of benefit and risk. The RBA helped to incorporate the risk and benefits of multiple treatments. Then, an incremental risk-benefit ratio was calculated by dividing the incremental risk by benefit using data from NMA, and they were jointly simulated using Monte Carlo methods. Finally, net clinical benefit (NCB) probability curves were constructed at varying acceptability thresholds.

Results: Seventy RCTs with hsPDA were eligible considering 13 different interventions, but data on presymptomatic PDA were not enough for pooling. The clustered ranking plot from NMA indicated that 3 interventions (i.e., high-dose oral ibuprofen, standard-dose oral acetaminophen, and standard-dose oral ibuprofen) yielded high PDA closure and low AE. These three treatments and additional commonly used indomethacin were considered in the RBA. Given an acceptable threshold of 25% or having one AE out of four PDA closures, high-dose oral ibuprofen had a 36% chance of having the highest NCB, followed by standard-dose oral acetaminophen (27%), and oral ibuprofen (23.7%). Subgroup analysis indicated that the chances of having the highest NCB of GA ≥28 weeks were similar to that of all available studies. The best for GA <28 weeks, no data for high-dose oral ibuprofen, was standard-dose oral acetaminophen, followed by standard-dose oral ibuprofen.

Conclusions: Trade-off RBA indicated that high-dose oral ibuprofen might be the best treatment for preterm, GA ≥28 weeks, with hsPDA followed by the standard-dose oral acetaminophen and ibuprofen. Preferably, optimal high doses, postnatal age to start treatment, and long-term outcomes are needed to study in the future.

Keywords: Acetaminophen; Hemodynamically significant patent ductus arteriosus; Ibuprofen; Indomethacin; Patent ductus arteriosus; Preterm; Risk-benefit analysis.