Systematic review and network meta-analysis of intravenous ibuprofen vs. intravenous indomethacin vs. placebo in the management of clinically and/or echocardiographically important patent ductus arteriosus in preterm infants at greater than 24 hours of life
Jones, Lisa Jane
Masters Research - Master of Philosophy (MPhil) Objectives: To evaluate the effects of indomethacin or ibuprofen compared with placebo on closure, morbidity and mortality in preterm infants <37 weeks’ gestation with echocardiographically and/or clinically important patent ductus arteriosus (PDA) at >24 h of life. Data sources: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, CINAHL, Cochrane Library, clinicaltrials.gov, controlled-trials.com, American Pediatric and European Paediatric Research Societies and Effective Care of the Newborn Infant. Review methods: Systematic review with network meta-analysis of randomised studies comparing intravenous indomethacin, ibuprofen or placebo for PDA in preterm infants at >24 h of life. Results: Ten trials compared intravenous indomethacin versus intravenous ibuprofen, nine compared intravenous indomethacin versus placebo and one intravenous ibuprofen versus placebo. Both intravenous indomethacin [pooled RR 2.39 (95% CI 2.05 to 2.78)] and intravenous ibuprofen [RR 2.40 (95% CI 2.03 to 2.84)] closed a PDA more effectively than placebo. Intravenous ibuprofen was associated with approximately 30% greater risk of chronic lung disease than intravenous indomethacin [RR 1.28 (95% CI 1.03 to 1.60)] or placebo [RR 1.29 (95% CI 0.99 to 1.70)]. Differences in risk or benefit were not significant between any combination of intravenous indomethacin, intravenous ibuprofen or placebo groups for intraventricular haemorrhage, necrotising enterocolitis and death. Reporting on neurological outcomes was insufficient for pooling. Sensitivity analyses indicate a gestational and post-natal age dependent effect on PDA closure and the risk of CLD. The majority of trials comparing intravenous indomethacin with placebo administered non-randomised rescue treatment to > 20% of the placebo group. Sample size estimations for intravenous indomethacin suggest large numbers are needed to provide adequate power to detect a difference in the risk of outcomes other than PDA closure. Smaller numbers are required for intravenous ibuprofen with a minimum of 131 per group for the outcome of CLD. Conclusions: Intravenous indomethacin or ibuprofen administered to preterm infants for PDA at >24 h of life promoted ductal closure, but other short-term benefits were not seen. Data from randomized trials concerning the effect of treatment with indomethacin or ibuprofen for PDA closure on IVH, CLD, NEC, survival and longer-term neurodevelopmental outcomes is presently insufficient to guide current practice. There is a need for well-designed good quality modern randomized controlled trials comparing intravenous ibuprofen and intravenous indomethacin administered for echo-targeted PDA and PDA detected by clinical signs in preterm infants at greater than 24 hours of life. Such trials should be multi-centre and incorporate improved methods of handling the administration of rescue treatment in the placebo group in order to improve the chance of detecting a benefit or risk. Data on longer-term respiratory and neurological outcomes are also urgently needed. Suggested trial methods include comparing early targeted at <24 hours with placebo randomised to either echo-targeted or symptomatic PDA as rescue at > 24 hours of life. Comparisons can then be made between the risk of outcomes in preterm infants with PDA receiving rescue treatment based on echo alone compared to those randomised to symptomatic rescue treatment but remaining untreated.