Meta-analysis: High-dose ibuprofen best bet for closing PDA in preterm infants
A high dose of oral ibuprofen appeared to be the best option for closing patent ductus arteriosus (PDA) in a meta-analysis of 4,802 preterm infants, researchers reported in JAMA.
PDA is an abnormal opening between the aorta and the pulmonary artery. It is a normal part of a baby’s circulatory system before birth but usually closes on its own within a few days of delivery. Large PDAs that remain open, however, can significantly impact blood flow and are sometimes treated with drug therapy.
For these latter cases, lead author Souvik Mitra, MD, and colleagues reported PDA closure was achieved in 67.4 percent of infants treated with indomethacin, ibuprofen or acetaminophen compared to 38 percent in the no-treatment group. A high dose of oral ibuprofen was associated with 3.59-fold greater odds of PDA closure than a standard dose of IV ibuprofen and 2.35-fold greater odds than a standard dose of IV indomethacin.
Importantly, placebo or non-treatment wasn’t associated with a statistically significant increase in mortality, necrotizing enterocolitis or intraventricular hemorrhage despite ranking worst in terms of PDA closure.
“This raises the question whether active pharmacological closure of hemodynamically significant PDA necessarily improves clinical outcomes,” wrote Mitra, with Dalhousie University in Canada, and colleagues. “With increasing emphasis on conservative management of PDA, these results may encourage researchers to revisit placebo-controlled trials against newer pharmacotherapeutic options.”
The authors included 68 randomized clinical trials in their meta-analysis. A standard dose of ibuprofen (either IV or oral) was defined as an initial 10 mg/kg followed by half that amount for two more doses. High-dose ibuprofen was defined as an initial 15 to 20 mg/kg followed by half that amount for two more doses.
Mitra et al. pointed out oral acetaminophen also ranked highly among studied interventions but behind high-dose oral ibuprofen.
“In contrast, the standard dose of intravenous ibuprofen generally ranked just above placebo across all effectiveness outcomes, suggesting that the standard intravenous doses may be ineffective in achieving PDA closure beyond the first few days of life,” they wrote, noting the standard dosing is based on old data, while more recent evidence has demonstrated the effectiveness or larger doses.
Mitra et al. also ran a meta-regression analysis to control for potential modifying effects such as gestational age, birth weight and year of study publication and found a high dose of ibuprofen still ranked atop the interventions they analyzed. In addition, a sensitivity analysis of only “high-quality” studies went against lingering fears about that intervention being associated with a higher risk for necrotizing enterocolitis.
“Despite supporting pharmacokinetic evidence, clinicians have often been reluctant to use oral ibuprofen formulations due to concerns about necrotizing enterocolitis,” the authors wrote. “In the sensitivity analysis of the high-quality studies, high-dose oral ibuprofen was associated with the best cumulative probability for preventing necrotizing enterocolitis, suggesting that hemodynamically significant PDA in itself is probably a significant risk factor for necrotizing enterocolitis and closing it successfully when hemodynamically significant could in turn reduce the risk of necrotizing enterocolitis.”
The researchers reiterated the need for further research powered to detect clinically important differences in treatment options for PDA. They cautioned their method of ranking interventions doesn’t necessarily imply that each higher-ranked treatment is statistically significantly better than a lower-ranked one.
Daniel joined TriMed’s Chicago editorial team in 2017 as a Cardiovascular Business writer. He previously worked as a writer for daily newspapers in North Dakota and Indiana.