Expectant Management or Early Ibuprofen for Patent Ductus Arteriosus.

BACKGROUND: Cyclooxygenase inhibitors are commonly used in infants with patent ductus arteriosus (PDA), but the benefit of these drugs is uncertain. METHODS: In this multicenter, noninferiority trial, we randomly assigned infants with echocardiographically confirmed PDA (diameter, >1.5 mm, with left-to-right shunting) who were extremely preterm (<28 weeks' gestational age) to receive either expectant management or early ibuprofen treatment. The composite primary outcome included necrotizing enterocolitis (Bell's stage IIa or higher), moderate to severe bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. The noninferiority of expectant management as compared with early ibuprofen treatment was defined as an absolute risk difference with an upper boundary of the one-sided 95% confidence interval of less than 10 percentage points. RESULTS: A total of 273 infants underwent randomization. The median gestational age was 26 weeks, and the median birth weight was 845 g. A primary-outcome event occurred in 63 of 136 infants (46.3%) in the expectant-management group and in 87 of 137 (63.5%) in the early-ibuprofen group (absolute risk difference, -17.2 percentage points; upper boundary of the one-sided 95% confidence interval [CI], -7.4; P<0.001 for noninferiority). Necrotizing enterocolitis occurred in 24 of 136 infants (17.6%) in the expectant-management group and in 21 of 137 (15.3%) in the early-ibuprofen group (absolute risk difference, 2.3 percentage points; two-sided 95% CI, -6.5 to 11.1); bronchopulmonary dysplasia occurred in 39 of 117 infants (33.3%) and in 57 of 112 (50.9%), respectively (absolute risk difference, -17.6 percentage points; two-sided 95% CI, -30.2 to -5.0). Death occurred in 19 of 136 infants (14.0%) and in 25 of 137 (18.2%), respectively (absolute risk difference, -4.3 percentage points; two-sided 95% CI, -13.0 to 4.4). Rates of other adverse outcomes were similar in the two groups. CONCLUSIONS: Expectant management for PDA in extremely premature infants was noninferior to early ibuprofen treatment with respect to necrotizing enterocolitis, bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. (Funded by the Netherlands Organization for Health Research and Development and the Belgian Health Care Knowledge Center; BeNeDuctus ClinicalTrials.gov number, NCT02884219; EudraCT number, 2017-001376-28.).

Multi-centre, randomised non-inferiority trial of early treatment versus expectant management of patent ductus arteriosus in preterm infants (the BeNeDuctus trial): statistical analysis plan.

BACKGROUND: Controversy exists about the optimal management of a patent ductus arteriosus (PDA) in preterm infants. A persistent PDA is associated with neonatal mortality and morbidity, but causality remains unproven. Although both pharmacological and/or surgical treatment are effective in PDA closure, this has not resulted in an improved neonatal outcome. In most preterm infants, a PDA will eventually close spontaneously, hence PDA treatment potentially increases the risk of iatrogenic adverse effects. Therefore, expectant management is gaining interest, even in the absence of convincing evidence to support this strategy. METHODS/DESIGN: The BeNeDuctus trial is a multicentre, randomised, non-inferiority trial assessing early pharmacological treatment (24-72 h postnatal age) with ibuprofen versus expectant management of PDA in preterm infants in Europe. Preterm infants with a gestational age of less than 28 weeks and an echocardiographic-confirmed PDA with a transductal diameter of > 1.5 mm are randomly allocated to early pharmacological treatment with ibuprofen or expectant management after parental informed consent. The primary outcome measure is the composite outcome of mortality, and/or necrotizing enterocolitis Bell stage ≥ IIa, and/or bronchopulmonary dysplasia, all established at a postmenstrual age of 36 weeks. Secondary short-term outcomes are comorbidity and adverse events assessed during hospitalization and long-term neurodevelopmental outcome assessed at a corrected age of 2 years. This statistical analysis plan focusses on the short-term outcome and is written and submitted without knowledge of the data. TRIAL REGISTRATION: ClinicalTrials.gov NTR5479. Registered on October 19, 2015, with the Dutch Trial Registry, sponsored by the United States National Library of Medicine Clinicaltrials.gov NCT02884219 (registered May 2016) and the European Clinical Trials Database EudraCT 2017-001376-28.

Conservative Management of Patent Ductus Arteriosus in Preterm Infants-A Systematic Review and Meta-Analyses Assessing Differences in Outcome Measures Between Randomized Controlled Trials and Cohort Studies.

Objective: This study aims to evaluate outcome after conservative management (no pharmacological/surgical intervention other than fluid restriction, diuretics, or ventilator adjustments) compared with active (pharmacological and/or surgical) treatment for patent ductus arteriosus (PDA) in preterm infants and analyze differences in outcome between randomized controlled trials (RCTs) and cohort studies. Study Design: This is a systematic literature review using PubMed, EMBASE, and Cochrane library. RCTs and cohort studies comparing conservative management with active treatment were included. Meta-analysis was used to compare conservative management with any active (pharmacological and/or surgical), any pharmacological (non-prophylactic and prophylactic), and/or surgical treatment for mortality as primary and major neonatal morbidity as secondary outcome measure. Fixed-effect analysis was used, unless heterogeneity (I 2) was >50%. Outcome is presented as relative risk (RR) with 95% confidence interval. Results: Twelve cohort studies and four RCTs were included, encompassing 41,804 and 720 patients, respectively. In cohort studies, conservative management for PDA was associated with a significantly higher risk for mortality (RR, 1.34 [1.12-1.62]) but a significantly lower risk for bronchopulmonary dysplasia (RR, 0.55 [0.46-0.65]), necrotizing enterocolitis (RR, 0.85 [0.77-0.93]), intraventricular hemorrhage (RR, 0.88 [0.83-0.95]), and retinopathy of prematurity (RR, 0.47 [0.28-0.79]) compared with any active PDA treatment. Meta-analysis of the RCTs revealed no significant differences in outcome between conservative management and active treatment. Conclusion: No differences in mortality or morbidity for conservative management compared with active treatment regimens were observed in RCTs. Findings from cohort studies mainly highlight the lack of high-quality evidence for conservative management for PDA in preterm infants.

Factors Associated With Benefit of Treatment of Patent Ductus Arteriosus in Preterm Infants: A Systematic Review and Meta-Analysis.

Context: There is an ongoing debate on the optimal management of patent ductus arteriosus (PDA) in preterm infants. Identifying subgroup of infants who would benefit from pharmacological treatment might help. Objective: To investigate the modulating effect of the differences in methodological quality, the rate of open-label treatment, and patient characteristics on relevant outcome measures in randomized controlled trials (RCTs). Data Sources: Electronic database search between 1950 and May 2020. Study Selection: RCTs that assessed pharmacological treatment compared to placebo/no treatment. Data Extraction: Data is extracted following the PRISMA guidelines. Outcome measures were failure to ductal closure, surgical ligation, incidence of necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, periventricular leukomalacia, intraventricular hemorrhage (IVH) grade ≥3, retinopathy of prematurity and mortality. Results: Forty-seven studies were eligible. The incidence of IVH grade ≥3 was lower in the treated infants compared to the placebo/no treatment (RR 0.77, 95% CI 0.64-0.94) and in the subgroups of infants with either a gestational age <28 weeks (RR 0.77, 95% CI 0.61-0.98), a birth weight <1,000 g (RR 0.77, 95% CI 0.61-0.97), or if untargeted treatment with indomethacin was started <24 h after birth (RR 0.70, 95% CI 0.54-0.90). Limitations: Statistical heterogeneity caused by missing data and variable definitions of outcome parameters. Conclusions: Although the quality of evidence is low, this meta-analysis suggests that pharmacological treatment of PDA reduces severe IVH in extremely preterm, extremely low birth weight infants or if treatment with indomethacin was started <24 h after birth. No other beneficial effects of pharmacological treatment were found.

Early treatment versus expectative management of patent ductus arteriosus in preterm infants: a multicentre, randomised, non-inferiority trial in Europe (BeNeDuctus trial).

BACKGROUND: Much controversy exists about the optimal management of a patent ductus arteriosus (PDA) in preterm infants, especially in those born at a gestational age (GA) less than 28 weeks. No causal relationship has been proven between a (haemodynamically significant) PDA and neonatal complications related to pulmonary hyperperfusion and/or systemic hypoperfusion. Although studies show conflicting results, a common understanding is that medical or surgical treatment of a PDA does not seem to reduce the risk of major neonatal morbidities and mortality. As the PDA might have closed spontaneously, treated children are potentially exposed to iatrogenic adverse effects. A conservative approach is gaining interest worldwide, although convincing evidence to support its use is lacking. METHODS: This multicentre, randomised, non-inferiority trial is conducted in neonatal intensive care units. The study population consists of preterm infants (GA < 28 weeks) with an echocardiographic-confirmed PDA with a transductal diameter > 1.5 mm. Early treatment (between 24 and 72 h postnatal age) with the cyclooxygenase inhibitor (COXi) ibuprofen (IBU) is compared with an expectative management (no intervention intended to close a PDA). The primary outcome is the composite of mortality, and/or necrotising enterocolitis (NEC) Bell stage ≥ IIa, and/or bronchopulmonary dysplasia (BPD) defined as the need for supplemental oxygen, all at a postmenstrual age (PMA) of 36 weeks. Secondary outcome parameters are short term sequelae of cardiovascular failure, comorbidity and adverse events assessed during hospitalization and long-term neurodevelopmental outcome assessed at a corrected age of 2 years. Consequences regarding health economics are evaluated by cost effectiveness analysis and budget impact analysis. DISCUSSION: As a conservative approach is gaining interest, we investigate whether in preterm infants, born at a GA less than 28 weeks, with a PDA an expectative management is non-inferior to early treatment with IBU regarding to the composite outcome of mortality and/or NEC and/or BPD at a PMA of 36 weeks. TRIAL REGISTRATION: This trial is registered with the Dutch Trial Register NTR5479 (registered on 19 October 2015), the registry sponsored by the United States National Library of Medicine Clinicaltrials.gov NCT02884219 (registered May 2016) and the European Clinical Trials Database EudraCT 2017-001376-28 .