MANUSCRIPT CITATION

Oncel MY, Yurttutan S, Erdeve O, Uras N, Altug N, Oguz SS, Canpolat FE, Dilmen U. Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: a randomized controlled trial. J Pediatr. 2014; 164:510-4. PMID: 24359938.

REVIEWED BY

Clyde J. Wright, MD
Assistant Professor
Children’s Hospital Colorado and University of Colorado School of Medicine

Sarah J. Ratcliffe, PhD
Associate Professor
Division of Biostatistics, University of Pennsylvania Perelman School of Medicine

TYPE OF INVESTIGATION

Treatment

QUESTION

P: In infants < 30 wks GA, < 1250 g, and postnatal age 48-96 hours with an echocardiographically confirmed hemodynamically significant PDA (hsPDA)
I: does oral paracetamol
C: compared to oral ibuprofen
O: increase ductal closure rates
T: when assessed at the end of treatment?

METHODS

• Design: Randomized controlled trial
• Allocation: Concealed by envelope randomization
• Blinding: Unclear if the treatment team (physician, nurses, etc.) were blinded. The pediatric cardiologist performing the echocardiographic evaluation was blinded to what treatment the infant had received.
• Follow-up period: Until hospital discharge (~70 days)
• Setting: Neonatal intensive care unit of Zekai Tahir Burak Maternity Teaching Hospital in Ankara, Turkey from February 2012 – December 2012
• Patients: Preterm infants with a gestational age < 30 weeks, birthweight < 1250 g, postnatal age 48-96 hours, and 1 of the following echocardiographic criteria: a duct size > 1.5 mm, a left atrium-to-aorta ratio >1.5, end diastolic reversal of blood flow in the aorta, or poor cardiac function in addition to clinical signs of a PDA. Exclusion criteria were the presence of major congenital abnormalities, right-to-left ductal shunting, life-threatening infection, grade III or grade IV IVH, urine output of less than 1 mL/kg/h during the preceding 8 hours, serum creatinine level >1.6 mg/ dL, platelet count <60 000/mm³, liver failure, hyperbilirubinemia requiring exchange transfusion, and persistent pulmonary hypertension.
• Intervention: Randomization to either oral paracetamol (15 mg/kg every 6 hours for 3 days) or oral ibuprofen (initial dose 10 mg/kg, followed by 5 mg/kg at 24 and 48 hours).
• Outcomes:
  • Primary outcome: The success rate of treatment, defined as closed duct on echocardiography after the complete course.
  • Secondary outcomes: The need for retreatment or surgical ligation of the PDA (performed for patients who had hsPDA after 2 completed courses of medical treatment), mode and duration of ventilation; increase in blood urea nitrogen, serum creatinine, bili- rubin, aspartate amino transferase, or ALT levels after treatment, rates of ductal reopening, surfactant treatment, pneumothorax, pulmonary hemorrhage, CLD, IVH, NEC (any stage, according to Bell classification), gastrointestinal bleeding, ROP (according to the International Classification), definite sepsis (clinical symptoms and signs of sepsis and a positive blood bacterial culture), and death. CLD was defined as a persistent oxygen requirement at 36 weeks post- menstrual age.
• Analysis and Sample Size: Assuming a closure rate of 83.3% with oral ibuprofen, the authors estimated that sample of 78 neonates were needed to detect a 25% difference in PDA closure rate with 80% power and type 1 error of 0.05.
• Patient follow-up: Of the 90 neonates randomized, 10 died prior to completing treatment (5 in each treatment arm). Thus, 80/90 (88.9%) were included in follow up.

MAIN RESULTS:

Of note, the authors have used ibuprofen as the reference group when calculating the RR for the entire study. However, for the subgroups (<28 wk and ≤26 wks, the authors have changed the reference group to the paracetamol group. This discrepancy in presenting their results explains the apparently contradictory RRs presented in this table.

CONCLUSION:

In neonates <30 wks and <1250 gm with hemodynamically significant PDA, rates of PDA closure following treatment with oral ibuprofen or oral paracetamol are similar.

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COMMENTARY:

Despite intense study, there is no consensus regarding management of the patent ductus arteriosus in the preterm neonate. It is likely that the lack of established diagnostic criteria contributes to the diverse strategies taken for PDA management.¹ Still, the association between PDA and adverse outcomes is well documented.^2,3 Unfortunately, aggressive strategies to decrease the incidence of PDA may lead to overtreatment and adverse effects related to this treatment.^4-6 Currently, pharmacologic management includes the use of ibuprofen and indomethacin, both prostaglandin H2 synthase inhibitors,³ with evidence supporting the use of ibuprofen over indomethacin.⁷ Thus, identifying more effective and safer treatment strategies to close the PDA in neonates is paramount.

In that regard, Oncel and colleagues have reported important work regarding the use of oral paracetamol to close the patent ductus arteriosus in a group of infants ≤30 wks gestation and ≤1250 grams. In this cohort of infants, both groups experienced relatively high treatment success defined as PDA closure after one course of therapy (Table 1). There were no reported differences between treatment groups in any of the a prior identified adverse effects.

Of note, the authors report a higher closure rate with paracetamol vs. ibuprofen in babies <26 wks. Given the small size of the trial, this difference was not statistically significant. The opposite directional effect seen in this subgroup compared to all infants is likely a reflection of variability. A test of heterogeneity of effect would indicate the three RRs presented did not significantly differ. However, as extremely premature infants are at highest risk of morbidities associated with PDA, and with complications of prostaglandin H2 synthase inhibitors, this result deserves further study.

The authors report that the study “was designed with sufficient power to determine if oral paracetamol and ibuprofen are equally efficacious and safe for PDA closure.” However, if paracetamol is to be considered “non-inferior” – a 25% lower closure rate is clinically unacceptable. As designed, the results of this trial do not demonstrate equivalence between ibuprofen and paracetamol, despite the author’s statement concluding otherwise. If the goal was to demonstrate an efficacious treatment effect, the study should have been designed as a non-inferiority trial. This would require setting the difference in the power calculation to the smallest possible difference that anyone could think of as clinically meaningful. To design a non-inferiority trial that resulted in a sample size of 78 under their assumptions of a closure rate of 83.3% with oral ibuprofen, 80% power, type 1 error of 0.05 and with an absolute difference of 25% being deemed not important, they would have had to further assume that oral paracetamol would have only increased the closure rate by at most 5%. Using a more reasonable absolute difference of 10% for determining importance, keeping all other assumptions the same, the sample size needed would increase to ~1200. Therefore, while these are important pilot data, broad conclusions regarding the efficacy of oral paracetamol cannot be made. The closure rate reported within this trial is also similar to a recently reported spontaneous closure rate among infants born before 28 weeks, which complicates interpretations even further.⁸

This trial also reported data on co-morbidities encountered in the NICU (NEC, sepsis, etc) and relevant laboratory data (serum bilirubin, AST, ALT). However, given the small numbers of babies treated with paracetamol reported in the literature to date, little is known regarding unanticipated adverse effects, particularly long-term.⁹ Thus, while important, given the small size of this trial, the safely of paracetamol in this patient population remains unclear.

The approach to PDA treatment remains variable and controversial. While most clinicians will agree that a hemodynamically significant ductus is problematic and should be closely watched and most likely treated, it is less clear how to predict which babies will close their PDA spontaneously, or will go to suffer complications related to that duct. The unwanted side effects associated with current treatment options further complicate this issue. Until we have more precise diagnostic and predictive tools, we will continue to unnecessarily expose babies who will not benefit from PDA-therapy to unnecessary risks. Thus, identifying and testing alternate treatment options – as done in this trial – must be encouraged and continued. An appropriately powered RCT comparing paracetamol and indomethacin/ibuprofen in a high-risk population of preterm infants should be pursued. Adding a placebo-treated arm into such a trial would be an option worth considering

REFERENCES

1. Zonnenberg I, de Waal K. The definition of a haemodynamic significant duct in randomized controlled trials: a systematic literature review. Acta Paediatr 2012;101:247-51.
2. Benitz WE. Learning to live with patency of the ductus arteriosus in preterm infants. J Perinatol 2011;31 Suppl 1:S42-8.
3. Heuchan AM, Clyman RI. Managing the patent ductus arteriosus: current treatment options. Arch Dis Child Fetal Neonatal Ed 2014;99:F431-6.
4. Schmidt B, Davis P, Moddemann D, et al. Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants. N Engl J Med 2001;344:1966-72.
5. Schmidt B, Roberts RS, Fanaroff A, et al. Indomethacin prophylaxis, patent ductus arteriosus, and the risk of bronchopulmonary dysplasia: further analyses from the Trial of Indomethacin Prophylaxis in Preterms (TIPP). J Pediatr 2006;148:730-4.
6. DeMauro SB, Schmidt B, Roberts RS. Why would a sane clinician not prescribe prophylactic indomethacin? Acta Paediatr 2011;100:636.
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8. Rolland A, Shankar-Aguilera S, Diomande D, Zupan-Simunek V, Boileau P. Natural evolution of patent ductus arteriosus in the extremely preterm infant. Arch Dis Child Fetal Neonatal Ed 2015;100:F55-8.
9. Ohlsson A, Shah PS. Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants. Cochrane Database Syst Rev 2015;3:CD010061.