Efficacy and Costs of Three Pharmacotherapies for Patent Ductus Arteriosus Closure in Premature Infants

Abstract

The hemodynamic impact of persistent patent ductus arteriosus (PDA) is associated with neonatal morbidities and mortality in preterm newborns. While there has been considerable debate about optimal management of PDA and its impact on clinical outcomes, there is widespread variation in practice, such as using different pharmacotherapies to achieve closure of hemodynamically significant PDA during the first week of life in very low birth weight infants. The objective was to estimate the efficacy of acetaminophen, ibuprofen, and indomethacin with regard to ductal closure and to compare the costs of these three commonly used medications to treat PDA in preterm infants. PubMed, Embase, and Cochrane Registry were searched for trials from the years 2010-2020. We identified 17 randomized clinical trials (RCTs) and 14 case series that enrolled preterm infants <37 weeks gestational age for inclusion. Pooled estimates of closure rates for acetaminophen (n = 630), ibuprofen (n = 694), and indomethacin (n = 312) were analyzed using the weighted proportion ratio using a Mantel‑Haenszel random effects model. The chi-squared test of proportions was used to determine significance between groups. We accessed cost estimates of pharmacotherapy from the Lexi-Comp average wholesale price database and utilized a decision tree model to appraise cost benefits for the outcome measure of successful PDA closure. The pooled proportional point estimates of closure rates from RCTs for acetaminophen, ibuprofen, and indomethacin were 70.1% (95% confidence interval [CI] 60-80), 63.4% (95% CI 52.8-74.1), and 71.5% (95% CI 62.3-80.7), respectively. There was no significant statistical difference in closure rates when RCTs and uncontrolled case series were combined. Pairwise comparisons showed both acetaminophen and indomethacin were each more effective in closing PDA than ibuprofen (acetaminophen vs indomethacin: p = 0.01; ibuprofen vs indomethacin: p = 0.02; acetaminophen vs indomethacin: p = 0.93). Comparing costs for successful closure of PDA, at the average wholesale price of different medications, suggested that treatment with acetaminophen costs significantly less, with a mean of $1487 (95% CI 1300-1737), compared to ibuprofen, with a mean of $2585 (95% CI 2214-3104), and indomethacin, with a mean of $2661 (95% CI 2358-3052), per course of treatment. Our meta-analysis suggests acetaminophen is non-inferior to both indomethacin and ibuprofen, and costs relatively less for successful PDA constriction in premature infants. Further clinical trials are warranted to compare acetaminophen's safety, along with short- and long-term effects, to help resolve the clinical conundrum of the necessity of early treatment in the management of PDA, and the optimal pharmacological course, if indicated.