Early Treatment of Patent Ductus Arteriosus with Ibuprofen

The Baby-OSCAR trial is a multicenter, double-blinded, randomized, placebo-controlled trial conducted to evaluate if ‘early selective treatment’ of patent ductus arteriosus (PDA) with intravenous ibuprofen at < 72 hours after birth is superior to ‘no early selective treatment’ in extremely preterm neonates born between 23 weeks 0 days’ and 28 weeks 6 days’ gestation [1]. Eligibility for inclusion in the study was determined by the presence of a large PDA that had a diameter of > 1.5 mm and an unrestricted, pulsatile, left-to-right blood flow. The intervention comprised three doses of ibuprofen (first dose - 10 mg/kg, second and third doses - 5 mg/kg each) administered intravenously at an interval of 24 hours. The placebo group received a similar volume of normal saline. As this was a double-blinded study, open-label treatment was allowed if strict criteria for the presence of a hemodynamically significant PDA were met. These criteria included the need for ventilator dependence for at least 7 continuous days and the presence of a large PDA on echocardiography. This essentially meant that open-label treatment could be given only after the study intervention, which was to be started within 72 hours of birth and continued for 3 days, was over. The study aimed to recruit a total of 730 neonates. The sample size was calculated to find a decrease in primary outcome from 60% to 48%, i.e., a 12% absolute reduction. The primary outcome of the study was a composite of death or moderate to severe bronchopulmonary dysplasia (BPD) at 36 weeks of postmenstrual age. The specificity of the outcome was improved by conducting a physiological challenge test to differentiate between mild and moderate BPD. The secondary outcomes included the individual components of the composite primary outcome and various neonatal morbidities including severe intraventricular hemorrhage, cystic periventricular leukomalacia, and pulmonary hemorrhage. Serious adverse events were also reported, both pre-specified in the protocol and unanticipated.

The study was able to recruit a total of 653 neonates with a mean (SD) gestation (weeks) of 26.1 (1.5) and 26.1 (1.6), and a mean (SD) birth weight (g) of 840 (205) and 853 (211) in the ibuprofen and placebo groups, respectively. The median age at the first intervention dose was 61 h in both study groups. In about two-thirds of neonates, the study intervention was initiated at 48–72 hours after birth, and in about one-fourth of neonates at 24–48 hours after birth. At the time of randomization, about three-fourths of neonates had a ductal diameter of at least 2 mm and about two-thirds were receiving invasive ventilation. The primary outcome - death or moderate or severe bronchopulmonary dysplasia (BPD) - was observed in 220 of 318 (69.2%) neonates in the ibuprofen group and 202 of 318 (63.5%) neonates in the placebo group (adjusted relative risk: 1.09; 95% CI: 0.98 to 1.20). Although PDA was more likely to be closed at 3 weeks after birth in the ibuprofen group, the incidence of other neonatal outcomes was similar in the two groups. No important differences were observed in pre-specified subgroup analyses based on gestation at birth, size of PDA at randomization, and mode of respiratory support at randomization. The authors concluded that early selective treatment of large PDA with ibuprofen was not associated with a lower risk of death or moderate or severe BPD in extremely preterm neonates.