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Oral ibuprofen boosts patent ductus arteriosus closure in preterm infants
Infants treated with a high dose of oral ibuprofen were more likely to have a hemodynamically significant patent ductus arteriosus closure compared with those treated with standard doses of IV indomethacin or IV ibuprofen, according to a systematic review and analysis published in JAMA.
Souvik Mitra, MD, assistant professor in the department of pediatrics at Dalhousie University in Nova Scotia, Canada, and colleagues analyzed data from 4,802 preterm infants with patent ductus arteriosus from 68 randomized trials. The trials analyzed the effects of an oral or IV formulation of ibuprofen, indomethacin or acetaminophen compared with placebo, another medication or no treatment on hemodynamically significant patent ductus arteriosus. Studies with prophylactic medication use or surgery as a primary treatment modality were excluded.
The primary outcome was hemodynamically significant patent ductus arteriosus closure up to 1 week after the first dose of the treatment. Closure was diagnosed clinically or by echocardiography. Secondary outcomes included mortality, surgical closure, intraventricular hemorrhage and necrotizing enterocolitis.
In all studies, treatment modalities included 14 different variations of ibuprofen, indomethacin or acetaminophen. Patent ductus arteriosus closure occurred in 67.4% of infants.
Infants treated with a high dose of oral ibuprofen were more likely to have patent ductus arteriosus closure compared with a standard dose of IV indomethacin (OR = 2.35; 95% credible interval [CrI], 1.08-5.31; absolute risk difference = 124 more per 1,000 infants; 95% CrI, 14-188) and a standard dose of IV ibuprofen (OR = 3.59; 95% CrI, 1.64-8.17; absolute risk difference = 199 more per 1,000 infants; 95% CrI, 95-258).
A high dose of oral ibuprofen was the best treatment option for patent ductus arteriosus closure (mean surface under the cumulative ranking [SUCRA] = 0.89; standard deviation = 0.12) and to reduce surgical patent ductus arteriosus ligation (mean SUCRA = 0.98; standard deviation = 0.08). Results were similar in sensitivity and meta-regression analyses.
Necrotizing enterocolitis, mortality or intraventricular hemorrhage did not significantly differ in infants treated with placebo or no treatment vs. other treatment modalities.
“The overall high-ranking probabilities across outcomes suggest that high and standard doses of oral ibuprofen and oral acetaminophen could be effective alternatives to the standard regimens of intravenous ibuprofen and intravenous indomethacin currently used to close a hemodynamically significant [patent ductus arteriosus],” Mitra and colleagues wrote. “Well-designed randomized clinical trials with optimal sample sizes to detect clinically important differences in effectiveness and safety using such medications are needed to confirm or refute the validity of the network meta-analysis results.” – by Darlene Dobkowski
Disclosures: The authors report no relevant financial disclosures.
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This study uses a relatively new way of analyzing studies, a network meta-analysis, the idea being that if treatment A vs. treatment B is compared in a randomized controlled trial and treatment B is compared to treatment C in a randomized controlled trial, then we can learn something about A vs. C.
Specifically, in this case, it’s important to have all the data about treatment of the patent ductus arteriosus in one analysis. It does not help with the primary question of whether we should treat the patent ductus arteriosus at all. This is the current issue at question in neonatology.
The findings suggest ibuprofen is better choice than our current standard of indomethacin.
A large randomized trial comparing prevention, treatment and no intervention with longer term outcomes into childhood is needed. The idea now is that maybe we don’t need to treat the patent ductus arteriosus at all, except when we try that, we end up having to treat babies in the NICU in real life.
To give you an idea of the controversy, two San Francisco neonatology groups have come to the exact opposite conclusions: Stanford — no efficacy data available to treat anyone (ie, no proof that treating the patent ductus arteriosus is associated with any benefit) and University of California, San Francisco — restarting a prophylaxis approach (treating everyone preventively).
There is still much research work to be done in this area. It is ripe for younger investigators.