Ibuprofen again failed to improve short-term outcomes when used to close patent ductus arteriosus (PDA) in newborns, the placebo-controlled Baby-OSCAR trial showed.
Administered parenterally a few days after infants were born premature, ibuprofen did not reduce the trial’s combined primary endpoint nor its individual components at 36 weeks of postmenstrual age:
- Mortality and moderate or severe bronchopulmonary dysplasia: 69.2% vs 63.5% with placebo (adjusted RR 1.09, 95% CI 0.98-1.20)
- Mortality: 13.6% vs 10.3% (adjusted RR 1.32, 95% CI 0.92-1.90)
- Moderate or severe bronchopulmonary dysplasia: 64.2% vs 59.3% (adjusted RR 1.09, 95% CI 0.96-1.23)
Study authors led by Samir Gupta, MD, of Sidra Medicine in Doha, Qatar, argued that they at least found no evidence that ibuprofen caused serious complications. Their report was published in the New England Journal of Medicine.
However, there were two serious adverse events possibly related to ibuprofen. One child experienced sudden deterioration with abdominal distention, hypotension, and severe metabolic acidosis (suspected necrotizing enterocolitis/bowel ischemia) and died the next day. Another baby had complications and died, the cause of death certified as severe pulmonary interstitial emphysema, extreme prematurity, acute renal failure, and Staphylococcal hemolyticus sepsis.
“The results of this latest randomized clinical trial validate those of previously conducted trials that have generated inconclusive data to support early ibuprofen administration,” commented Jill Maron, MD, MPH, of Women and Infants Hospital of Rhode Island and Warren Alpert Medical School of Brown University, Providence, in an accompanying editorial.
For example, in 2022, the BeNeDuctus study group had reported that early ibuprofen administration did not help clinical outcomes in this setting. Waiting for the PDA to close on its own was associated with non-inferior, perhaps even better clinical outcomes in that randomized trial — suggesting that an attempt to close the PDA with ibuprofen may be more harmful than the PDA itself.
The Baby-OSCAR investigators highlighted several differences between their trial — testing one course of ibuprofen in mostly babies on invasive ventilation — and BeNeDuctus’ preponderance of infants on noninvasive respiratory support who received repeated high-dose courses of the drug.
“Early exposure to high cumulative doses of ibuprofen in infants with a relatively low baseline risk of bronchopulmonary dysplasia, as in that trial, may be detrimental,” they suggested.
PDA is the most common cardiac anomaly in preterm infants. It is a persistent opening in the heart where the vessel connecting the aorta and the pulmonary artery does not close normally and results in a left-to-right shunt. This shunting has been associated with increased risk of bronchopulmonary dysplasia, pulmonary hemorrhage, intraventricular hemorrhage, necrotizing enterocolitis, and death.
“Despite extensive research to determine the appropriate timing for pharmacologic, nonpharmacologic, transcatheter, and surgical approaches to close the duct, there is currently no definitive, successful approach that reduces morbidity and optimizes short- and long-term outcomes in the preterm infant population,” Maron wrote.
She noted that drugs carry risks of side effects such as bleeding and renal injury, and the transcatheter Amplatzer Piccolo Occluder is not widely available. “Thus, the field continues to search for the appropriate approach to timely duct closure, with many centers opting for conservative management and limiting treatment to the most symptomatic infants.”
Baby-OSCAR was a randomized trial conducted across 32 neonatal intensive care units in the U.K.
Participants were 653 babies born extremely preterm (before 29 weeks’ gestation) with a large PDA (measuring at least 1.5 mm wide with left-to-right shunting). They were assigned a course of placebo or ibuprofen administered parenterally (loading dose 10 mg/kg followed by two doses of 5 mg/kg at least 24 hours apart). Infants had been randomized at a median age of 57 hours and gestational age 26 weeks.
Maternal and infant baseline characteristics were well balanced between the groups. Mother’s age averaged 30 years, and nearly three-quarters were white women. Boys accounted for 55% of the babies. Median Apgar score 5 minutes after birth was 8.0, and the median PDA diameter was 2.2 mm.
The first dose of ibuprofen or placebo was administered at a median of 61 hours after birth, which is fairly late compared with other trials.
A closed or small PDA, confirmed by echocardiography at 3 weeks of age, was achieved by 55.5% of the ibuprofen group compared with 37.0% of controls (adjusted RR 1.50, 95% CI 1.30-1.74).
“In spite of strict criteria to restrict its use, open-label therapy was received by 29.8% of the infants in the placebo group, the likely effect of which would have been to increase the percentage of infants with PDA closure in this group and make it more difficult to identify between-group differences in clinical outcomes,” Gupta and colleagues acknowledged.
They also noted that they were unable to meet their original enrollment goal of 730 patients. Moreover, it remains unclear if earlier intervention would have produced better results for ibuprofen.
The trial was funded by the National Institute for Health Research Health Technology Assessment Programme.
Gupta and Maron had no disclosures.
New England Journal of Medicine
Source Reference: Gupta S, et al “Trial of selective early treatment of patent ductus arteriosus with ibuprofen” New Engl J Med 2024; DOI: 10.1056/NEJMoa2305582.
New England Journal of Medicine
Source Reference: Maron JL “Patent ductus arteriosus — to close or not to close?” New Engl J Med 2024; DOI: 10.1056/NEJMe2313738.
Source link : https://www.medpagetoday.com/cardiology/prevention/108403
Publish date : 2024-01-24 17:00:00
Copyright for syndicated content belongs to the linked Source.