The Cochrane Library and treatment of patent ductus arteriosus: an overview of reviews

Background Patent ductus arteriosus (PDA), the condition in which the ductus arteriosus (DA) does not close, is a common problem in preterm and low birth weight infants. It is associated with significant mortality and morbidity in these children. Objectives To critically evaluate the evidence available in the Cochrane Library regarding the treatment of PDA with ibuprofen (IBU) and indomethacin (INDO) in preterm and/or low birth weight infants. Methods The Cochrane Library was searched using the term ‘patent ductus arteriosus.’ Reviews discussing pharmacological interventions with IBU and INDO in premature infants were included. Data on clinically important outcomes were extracted by one author and independently evaluated. Primary outcomes pre‐specified for inclusion in this overview were: failure to close a PDA, reopening of the ductus arteriosus after initial closure, need for retreatment/need for surgical closure and symptomatic PDA. Main results Four reviews, containing 31 trials and 1739 participants, were included in this overview. In these reviews five unique comparisons were indentified: IBU versus placebo or no treatment, IBU versus INDO, prolonged versus short course of INDO, INDO versus placebo for asymptomatic PDA, and continuous versus bolus INDO for symptomatic PDA. Of the primary outcomes, IBU decreased need for retreatment [risk ratio (RR) 0.38, 95% confidence interval (CI) 0.19 to 0.75; risk difference (RD) − 0.22, 95% CI − 0.36 to − 0.08; number needed to treat (NNT) = 6] and INDO reduced the rate of subsequent symptomatic PDA (RR 0.36, 95% CI 0.19 to 0.60; RD − 0.36, 95% CI − 0.52 to − 0.17; NNT = 5) when each was compared to placebo. Other primary outcomes (failure to close PDA, reopening of DA after closure and need for surgical ligation) were not statistically significant in any of the reviews in which they were reported. One review compared length of INDO treatment and showed that infants receiving shorter courses of drug had fewer episodes of necrotizing enterocolitis (NEC) (RR 1.87, 95% CI 1.07 to 3.27; RD 0.08, 95% CI 0.01 to 0.15; NNT = 15). Another review addressed efficacy of continuous versus bolus dose INDO in preterm infants with a symptomatic PDA. No statistically significant differences were found between these two regimens. In a separate review IBU was compared with placebo and with INDO for treatment of PDA. Twenty trials were included in the comparison of IBU versus INDO. The two drugs showed no difference in failure to close a PDA (RR 0.94, 95% CI 0.76 to 1.17); however, use of IBU was associated with a lower risk of NEC (RR 0.68, 95% CI 0.47 to 0.99; RD, − 0.04, 95% CI − 0.08 to 0.00; NNT = 27) as compared with INDO. Authors' conclusions Although both INDO and IBU successfully close the DA, our overview found no evidence of significant difference between these two drugs for the majority of outcomes reported. If medical treatment is undertaken for closure, there is no significant difference in rate of failure to close the PDA between INDO and IBU. There is an advantage to IBU as there is less association with NEC, although the magnitude of this benefit is small. If INDO is used it should be a short course, again to decrease the risk of NEC.