Investigators from multiple institutions conducted a randomized controlled trial to determine if expectant management is non-inferior to early treatment with ibuprofen in extremely premature infants with patent ductus arteriosus (PDA). Study participants were infants born at <28 weeks’ gestation with echocardiographically confirmed PDA with a diameter >1.5 mm and left-to-right shunt, diagnosed between 24 and 72 hours of life, who were treated at 1 of 17 NICUs in the Netherlands, Belgium, and Denmark. At enrollment, these participants were randomized to expectant management with no treatment for closing the PDA or ibuprofen therapy with randomization stratified by gestational age (<26 weeks or ≥26 weeks). The ibuprofen regimen was based on local protocol, with a goal of initiating treatment within 3 hours after randomization. The primary outcome was a composite of necrotizing enterocolitis, moderate-to-severe BPD (based on standardized criteria), or death at 36 weeks’ postmenstrual age. Expectant management was considered to be non-inferior to early ibuprofen treatment if the upper limit of the 1-sided 95% confidence interval (CI) of the absolute risk difference for the primary outcome was <10 percentage points. Secondary outcomes included each of the individual components of the composite primary outcome. The risk ratios (RR) for the 2 treatment groups were compared for each of these outcomes.
Data were analyzed on 273 infants, including 136 randomized to the expectant management group and 137 to the early ibuprofen group. The median gestational age of all participants was 26.1 weeks, and median birth weight was 845 grams. For those in the ibuprofen group, treatment was initiated at a median postnatal age of 63 hours and median initial dose of 10 mg/kg with 2 subsequent doses of 5 mg/kg. At 36 weeks’ postmenstrual age, a primary composite outcome event occurred in 63 infants (46.3%) in the expectant management group and 87 (63.5%) of those randomized to ibuprofen (risk difference, -17.2 percentage points; upper limit of 95% CI, -7.4), thus meeting the non-inferiority criterion. Overall, the risk of a primary outcome event was significantly lower in those in the expectant management group compared to infants treated with ibuprofen (RR, 0.73; 95% CI, 0.59, 0.71). There was no difference in the rate of necrotizing enterocolitis between the 2 groups (17.6% and 15.3%, respectively, for those in the expectant management and ibuprofen treatment groups; RR, 1.15; 95% CI, 0.67, 1.97), but moderate-to-severe BPD was less common in infants randomized to expectant care (rates 33.3% and 50.9%, respectively; RR, 0.66; 95% CI, 0.48, 0.90). Among those receiving expectant management, 19 (14.0%) died by 36 weeks’ postmenstrual age vs 25 (18.2%) infants in the ibuprofen group (RR, 0.77; 95% CI, 0.48, 1.32).
The authors conclude the expectant management was non-inferior to early ibuprofen treatment in extremely premature infants with PDA.
Dr Goldberg has disclosed no financial relationship relevant...