Expectant Management of PDA vs Early Ibuprofen in Preterm Infants

Expectant management is noninferior to early ibuprofen prophylaxis for necrotizing enterocolitis, bronchopulmonary dysplasia, or death at 36 weeks’ postmenstrual age in extremely premature infants with patent ductus arteriosus (PDA), according to a study in the New England Journal of Medicine.

The randomized, controlled, noninferiority BeNeDuctus (Early Treatment Versus Expectative Management of PDA in Preterm Infants; ClinicalTrials.gov Identifier: NCT02884219) trial was conducted at 17 neonatal intensive care units in the Netherlands, Belgium, and Denmark.

Participants were infants with extremely premature birth (gestational age <28 weeks) and echocardiographically confirmed PDA with a diameter of wider than 1.5 mm at the smallest point and a transductal left-to-right shunt between 24 and 72 hours postnatal age. They were randomly assigned to receive expectant management or early ibuprofen. In the expectant management group, no treatment was initiated to close the PDA.

The primary outcome was a composite of necrotizing enterocolitis (Bell stage IIa or higher), moderate-to-severe bronchopulmonary dysplasia, or death at a postmenstrual age of 36 weeks. The noninferiority of expectant management vs early ibuprofen treatment was defined as an absolute risk difference with an upper boundary of the 1-sided 95% CI of less than10 percentage points.

A total of 273 infants were randomly assigned to either the expectant management group (n=136) and the early ibuprofen group (n=137). The infants had an overall median gestational age of 26.1 (IQR, 25.1-27.0) weeks and a median birth weight of 845 (IQR, 724-980) grams.

Data for the composite primary outcome were available for all 273 infants at 36 weeks’ postmenstrual age. A primary outcome event occurred in 63 infants in the expectant management group and in 87 infants in the early ibuprofen group (absolute risk difference, -17.2 percentage points; upper boundary of the 1-sided 95% CI, -7.4; P <.001).

No material between-group differences were found regarding the incidence of necrotizing enterocolitis and death. In the intention-to-treat analysis, death occurred in 19 infants in the expectant management group and in 25 infants in the early ibuprofen group (absolute risk difference, -4.3 percentage points; 2-sided 95% CI, −13.0 to 4.4).

Necrotizing enterocolitis was observed in 24 infants in the expectant management group and in 21 infants in the early ibuprofen group (absolute risk difference, 2.3 percentage points; 95% CI, -6.5 to 11.1). Moderate-to-severe bronchopulmonary dysplasia occurred in 39 infants in the expectant management group and in 57 infants in the early ibuprofen treatment group (absolute risk difference, -17.6 percentage points; 95% CI, -30.2 to -5.0).

Adverse events occurred in 5.1% of infants in the expectant management group and in 5.8% of those in the early ibuprofen group. Serious adverse events occurred in 2.2% of infants in the expectant management group and in 2.9% in the early ibuprofen group.

The composite primary outcome occurred in 60 of 133 infants in the expectant management group vs 83 of 132 in the early ibuprofen group in the per-protocol analysis (absolute risk difference, -17.8 percentage points; upper boundary of the 1-sided 95% CI, -7.9; P <.001).

In a predefined sensitivity analysis with use of a modified classification of bronchopulmonary dysplasia, a primary outcome event occurred in 53 infants in the expectant management group and in 68 infants in the early ibuprofen group.

The researchers noted that enrollment was stopped after 48% of the planned sample size had undergone randomization, and the PDA diameter used is an imperfect indicator of hemodynamically significant PDA. In addition, the trial was unblinded, and a majority of infants were White and had a gestational age of older than 24 weeks at randomization.

“…expectant management for a PDA measuring more than 1.5 mm in diameter was noninferior to early ibuprofen treatment with regard to necrotizing enterocolitis, moderate-to-severe bronchopulmonary dysplasia, or death, and results suggested a lower risk of this outcome in the expectant-management group,” wrote the study authors.

This article originally appeared on The Cardiology Advisor