No Intervention as Good as Oral Ibuprofen for Patent Ductus Arteriosus in Preemies

By Megan Brooks

June 17, 2020

NEW YORK (Reuters Health) - For preterm infants with significant patent ductus arteriosus (PDA), doing nothing seems to work as well as giving oral ibuprofen, according to a randomized controlled noninferiority trial.

The two approaches resulted in similar rates of bronchopulmonary dysplasia (PDA) or death (the primary outcome) and no differences in ductal-closure rates before discharge.

"I do hope clinicians take home from the study that nonintervention approach is as good as standard medical therapy for PDA in preterm infants," Dr. Won Soon Park of Samsung Medical Center and Sungkyunkwan University School of Medicine, in Seoul, South Korea, told Reuters Health by email.

The findings are based on 142 preterm infants with hemodynamically significant PDA (ductal size >1.5 mm plus respiratory support) diagnosed between postnatal days 6 and 14. Infants were stratified by gestational age (GA 23-26 weeks and 27-30 weeks), and 70 received oral ibuprofen (initial dose of 10 mg/kg followed by a 5-mg/kg dose after 24 hours and a second 5-mg/kg dose after 48 hours) and 72 who received placebo (no intervention).

Ibuprofen significantly enhanced the ductal closure rate at one week compared with no intervention in the 27- to 30-week GA subgroup (34% vs. 7%; P=0.007), but not in the 23- to 26-week GA subgroup (8% vs. 2%; P=0.34). There was no significant difference in ductal-closure rates before hospital discharge (89% with ibuprofen vs. 82%, P=0.27), however.

In addition, no intervention was noninferior to ibuprofen for the primary composite outcome of BPD incidence or death (44% vs. 50%, respectively; 95% confidence interval, -0.11 to 0.22; noninferiority margin -0.2; P=0.51).

One infant in the ibuprofen arm received oral ibuprofen backup rescue treatment due to cardiopulmonary compromise that failed to respond to conservative management, and another infant in the ibuprofen arm underwent surgical ligation. None of the infants in the placebo arm received backup treatment.

The researchers note in their JAMA Pediatrics paper that the noninferiority of no intervention over drug treatment might be due to the low efficacy of oral ibuprofen for closing PDA, especially in the infants with GA 23 to 26 weeks.

"Although higher odds of PDA closure have been reported with oral ibuprofen than with intravenous ibuprofen or indomethacin, further studies using other NSAIDs are necessary to clarify whether there is a variation in the effectiveness of NSAIDs for closing PDA and thereby improving BPD or death," they write.

A limitation of their trial is its single-center design and a relatively large noninferiority margin that limited the power to detect small differences in the efficacy of the treatments according to stratified GA subgroups, they note.

Other limitations are the arbitrary definition of hemodynamically significant PDA defined only on the basis of the PDA size and respiratory assistance dependency and the lack of long-term neurodevelopmental outcome data.

Despite these limitations, "I think our results might alter the standard practice from medical therapy with non-steroidal anti-inflammatory agents and/or surgical ligation to conservative nonintervention approach for PDA in preterm infants," Dr. Park told Reuters Health.

The study had no commercial funding and the authors have declared no relevant conflicts of interest.

SOURCE: JAMA Pediatrics, online June 15, 2020.