Indomethacin, Ibuprofen, or Acetaminophen for Closure of PDA in Preterm Infants

Study Questions:

What is the relative likelihood of hemodynamically significant patent ductus arteriosus (PDA) closure with common pharmacotherapeutic interventions and their adverse event rates?


The investigators searched the databases of MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception until August 15, 2015, and updated on December 31, 2017, along with conference proceedings up to December 2017. Randomized clinical trials that enrolled preterm infants with a gestational age younger than 37 weeks treated with intravenous or oral indomethacin, ibuprofen, or acetaminophen versus each other, placebo, or no treatment for a clinically or echocardiographically diagnosed hemodynamically significant PDA were included. Data were independently extracted in pairs by six reviewers and synthesized with Bayesian random-effects network meta-analyses. The primary outcome was hemodynamically significant PDA closure, and secondary outcomes included need for surgical closure, mortality, necrotizing enterocolitis, and intraventricular hemorrhage.


In 68 randomized clinical trials of 4,802 infants, 14 different variations of indomethacin, ibuprofen, or acetaminophen were used as treatment modalities. The overall PDA closure rate was 67.4% (2,867 of 4,256 infants). A high dose of oral ibuprofen was associated with a significantly higher odds of PDA closure versus a standard dose of intravenous ibuprofen (odds ratio [OR], 3.59; 95% credible interval [CrI], 1.64-8.17; absolute risk difference, 199; 95% CrI, 95-258 more per 1,000 infants) and a standard dose of intravenous indomethacin (OR, 2.35; 95% CrI, 1.08-5.31; absolute risk difference, 124; 95% CrI, 14-188 more per 1,000 infants). Based on the ranking statistics, a high dose of oral ibuprofen ranked as the best pharmacotherapeutic option for PDA closure (mean surface under the cumulative ranking [SUCRA] curve, 0.89; standard deviation [SD], 0.12) and to prevent surgical PDA ligation (mean SUCRA, 0.98 [SD, 0.08]). There was no significant difference in the odds of mortality, necrotizing enterocolitis, or intraventricular hemorrhage with use of placebo or no treatment compared with any of the other treatment modalities.


The authors concluded that a high dose of oral ibuprofen was associated with a higher likelihood of hemodynamically significant PDA closure versus standard doses of intravenous ibuprofen or intravenous indomethacin.


This network meta-analysis reports that a high dose of oral ibuprofen was found to be associated with the best odds of hemodynamically significant PDA closure among all available pharmacotherapeutic options. Furthermore, placebo or no treatment was not associated with a higher odds of death, necrotizing enterocolitis, or intraventricular hemorrhage compared with any other treatment modality. This raises the issue of whether active pharmacological closure of hemodynamically significant PDA necessarily improves clinical outcomes. These results should give researchers equipoise to conduct placebo-controlled trials compared with newer pharmacotherapeutic options.

Clinical Topics: Cardiac Surgery, Congenital Heart Disease and Pediatric Cardiology, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Cardiac Surgery and Arrhythmias, Cardiac Surgery and CHD and Pediatrics, Congenital Heart Disease, CHD and Pediatrics and Arrhythmias, CHD and Pediatrics and Imaging, CHD and Pediatrics and Interventions, CHD and Pediatrics and Quality Improvement, Statins, Interventions and Imaging, Interventions and Structural Heart Disease, Echocardiography/Ultrasound

Keywords: Acetaminophen, Cardiac Surgical Procedures, Ductus Arteriosus, Patent, Echocardiography, Enterocolitis, Necrotizing, Gestational Age, Heart Defects, Congenital, Hemorrhage, Ibuprofen, Indomethacin, Infant, Newborn, Infant, Premature, Primary Prevention, Risk

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