What is the optimal treatment of a patent ductus arteriosus in preterm infants?

OBJECTIVE
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) <28 weeks. Studies have shown that the actual approach with medical and/or surgical treatment of a PDA does not reduce mortality or major neonatal morbidity. This implies that this high risk population might be over-treated with an increased iatrogenic risk of adverse effects related to the used drugs and/or surgery. An expectative approach is gaining interest, although convincing evidence is still lacking.


HYPOTHESIS
An expectative management (‘watchful waiting’) is not inferior regarding the composite of mortality and/or necrotizing enterocolitis (NEC) and/or bronchopulmonary dysplasia (BPD) in comparison with an early treatment regime in preterm infants with a PDA.


STUDY DESIGN
Multicenter, randomized, non-inferiority study.


STUDY POPULATION
Preterm infants (<28 weeks) with an echocardiographically confirmed PDA with a transductal diameter >1.5 mm.


INTERVENTION
Expectative PDA management is characterized as ‘watchful waiting’. No intervention is initiated with the intention to close a PDA.


USUAL CARE
A PDA is treated with cyclooxygenase-inhibitors (COXi), which is the actual standard care in preterm infants with GA<28 weeks, and if necessary surgical ligation.


OUTCOME MEASURES
The primary outcome is the composite of mortality and/or NEC and/or BPD. Secondary outcome parameters are short term sequelae of cardiovascular failure, adverse effects during the stay in the hospital and long-term neurodevelopmental consequences assessed at an corrected age of 2 years.


SAMPLE SIZE CALCULATION
With an estimated a priori risk for the primary outcome of 35%, type I error 5%, power 80% and non-inferiority, defined as a difference between the arms <10%, a sample size of 282 patients is needed in each arm.


COST-EFFECTIVENESS ANALYSIS/ BUDGET IMPACT ANALYSIS
It is anticipated that an expectative PDA management will be cost-effective from a societal perspective with an annual budgetary saving of about €800.000, based on reduction in medical treatments and diagnostics.

An expectative management ('watchful waiting') is not inferior regarding the composite of mortality and/or necrotising enterocolitis and/or bronchopulmonary dysplasia in comparison with an early treatment regime in preterm infants with a patent ductus arteriosus.

Primary outcome at a postmenstrual age of <= 36 completed weeks

Neurodevelopment at a corrected age of 2 years

Patients randomized to the expectative management arm will not receive any cyclooxygenase-inhibition and PDA management in this group can be characterized as 'watchful waiting'.

When the patient is allocated to the medical treatment arm cyclooxygenase-inhibition is prescribed (Indomethacin or Ibuprofen). When the ductus arteriosus has remained patent after the first course of cyclooxygenase-inhibition, a second course is started.