Hundscheid T, Onland W, Kooi EMW, Vijlbrief DC, de Vries WB, Dijkman KP, van Kaam AH, Villamor E, Kroon AA, Visser R, Mulder-de Tollenaer SM, De Bisschop B, Dijk PH, Avino D, Hocq C, Zecic A, Meeus M, de Baat T, Derriks F, Henriksen TB, Kyng KJ, Donders R, Nuytemans DHGM, Van Overmeire B, Mulder AL, de Boode WP; BeNeDuctus Trial Investigators. Expectant Management or Early Ibuprofen for Patent Ductus Arteriosus. N Engl J Med. 2022 Dec 6. doi: 10.1056/NEJMoa2207418. Epub ahead of print. PMID: 36477458

REVIEWED BY

Elena Itriago, M.D.
Assistant Professor
Baylor College of Medicine, Houston, TX, United States
Email: earaujo@bcm.edu

Daniela Dinu, M.D.
Associate Professor
Baylor College of Medicine, Houston, TX, United States
Email: Daniela.dinu@bcm.edu

CORRESPONDING AUTHOR

Daniela Dinu, M.D.
Associate Professor
Baylor College of Medicine, Houston, TX, United States
Email: Daniela.dinu@bcm.edu

TYPE OF INVESTIGATION

Treatment

QUESTION

In extremely preterm infants < 28 weeks gestational age with echocardiographically confirmed PDA detected between 24- and 72-hours postnatal age with a diameter > 1.5mm with left-to-right shunt (P), would expectant management (I) compared to early ibuprofen treatment (C) be non-inferior for the composite primary outcome of the development of necrotizing enterocolitis, moderate-to-severe bronchopulmonary dysplasia, or death at 36 weeks postmenstrual age (T)?

METHODS

• Design: an open-label, randomized controlled trial
• Allocation: infants were randomized in block sizes that varied within a range of 4 to 8 using a central web randomization system, stratified by recruiting center and gestational age (<26 weeks or ≥26 weeks)
• Blinding: not feasible
• Follow-up period: 36 weeks postmenstrual age for the primary composite outcome. For the expectant-management group, an unblinded echocardiography was allowed if indicated by the local pediatric cardiologist or after 36 weeks. An echocardiographic evaluation was performed at least 12 hours after the last dose for the early-ibuprofen group.
• Setting: 17 neonatal intensive care units in the Netherlands, Belgium, and Denmark
• Patients: 273 randomly assigned
  • Inclusion criteria:
    • GA < 28 weeks
    • PDA confirmed by echocardiogram with a diameter of > 1.5 mm and transductal left-to-right shunt between 24- and 72-hours postnatal age
    • Parental written informed consent
  • Exclusion criteria:
    • Contraindication to the administration of ibuprofen
    • Use of a cyclooxygenase inhibitor before randomization
    • Persistent pulmonary hypertension
    • Congenital heart defect (other than PDA or PFO)
    • Life-threatening congenital defect or chromosomal abnormality
    • Congenital anomaly that was associated with abnormal neurodevelopmental outcome
  • Intervention: ibuprofen administrated intravenously: 10mg/kg/dose for the first dose followed by 5 mg/kg/dose for the subsequent two doses 24 and 48 hours after first dose. A second dose of ibuprofen could be given if closure has not been achieved (defined as ductus that could not be visualized or had a diameter <0.5 mm).
  • Outcomes:
    • Primary outcome: composite of necrotizing enterocolitis, moderate-to-severe bronchopulmonary dysplasia, or death at 36 weeks postmenstrual age.
    • Secondary outcomes:
      • Surgical PDA ligation
      • Death at 28 days
      • Pulmonary hemorrhage
      • Pulmonary air leakage: pneumothorax and pulmonary interstitial emphysema
      • Use of cardiovascular support such as volume expansion, inotropes or vasopressors, and glucocorticoids
      • Renal failure
      • Intraventricular hemorrhage
      • Sepsis
      • Treatment for retinopathy of prematurity
      • Use of the following cointerventions: glucocorticoids, paracetamol, and diuretics
      • Time until full enteral feeds
      • The use of other support, such as supplemental oxygen and the use of invasive and noninvasive respiratory support
    • Analysis and Sample Size: for the primary analysis, the authors defined the noninferiority of expectant management as an absolute risk difference compared with early ibuprofen treatment with an upper boundary of the one-sided 95% confidence interval of less than 10 %. The authors used an estimated a priori risk for a primary-outcome event of 35%, a type I error of 5% and a power of 80% and determined that a sample size of 564 patients would be required. The trial was ended before the anticipated sample size had been reached because of the discontinuation of funding and slower-than-anticipated recruitment.
      • The authors performed an intention-to-treat analysis that included all the patients who underwent randomization and a per-protocol analysis that included infants in the expectant-management group who had received open-label pharmacologic treatment.
      • Additionally, the authors excluded infants in the early-ibuprofen group that did not receive ibuprofen. 1600 infants born at GA < 28 weeks were assessed for eligibility, 442 had parental informed consent, and 273 were randomized
      • 136 were assigned to expectant management, 135 received the allocated intervention, and 1 received open-label treatment
      • 137 were assigned to early ibuprofen treatment, 135 received assigned intervention, and two did not receive ibuprofen
    • Patient follow-up: 136 were included in the intention-to-treat analysis in the expectant management, and 133 were included in the per-protocol analysis. For the early ibuprofen treatment, 137 were included in the intention-to-treat analysis and 132 in the per-protocol analysis.

MAIN RESULTS

The baseline characteristics of the infants and their mothers were similar (Table 1).

In the early-ibuprofen group, ibuprofen was given at a median postnatal age of 63 hours. The composite primary outcome occurred in 63 of 136 infants (46.3%) in the expectant-management group and 87 of 137 infants (63.5%) in the early-ibuprofen group, with an absolute risk difference of -17.2 percentage p<0.001) (table 2).

No differences in necrotizing enterocolitis and death were observed regarding the secondary outcomes. Moderate-to-severe bronchopulmonary dysplasia was diagnosed in 29 of 117 infants (33.3%) in the expectant-management group and 57 of 112 infants (50.9%) in the early-ibuprofen group. There was no difference in the frequencies of adverse events between both groups.

CONCLUSION

The authors conclude that expectant management of PDA in preterm infants was non-inferior to early-ibuprofen treatment for a combined primary outcome of: necrotizing enterocolitis (stage Bell 2a or higher), moderate to severe bronchopulmonary dysplasia, or death at 36 weeks PMA.

COMMENTARY

PDA management remains one of the biggest conundrums in modern neonatology. A recent meta-analysis concluded that early treatment (within 7 days of life [DOL]) of a hemodynamically significant PDA (hs-PDA) might increase NSAID exposure without reducing CLD, severe IVH or NEC. Very early treatment (within 3 DOL) probably does not reduce surgical PDA ligation, severe IVH, or NEC and may not reduce CLD or neurodevelopmental impairment. (1)

 

Compared to conservative management, pharmacologic treatment at an average of 7 DOL of moderate-to-large PDA in infants < 28 weeks GA did not reduce PDA ligations or PDA at discharge, and no differences in NEC, BPD, death or need for respiratory support were found (2). Additionally, prophylactic targeted treatment between 6-12 hours after birth did not decrease the incidence of cerebral palsy in infants  < 28 weeks (3).

 

In the current study, expectant management of PDA >1.5 mm by echocardiogram in infants <26 weeks in the first 72 hours of life was non-inferior to ibuprofen treatment, while raising concerns about potential harm. This targeted prophylaxis trial had as the only inclusion criteria the echocardiographic PDA size and did not include other surrogate markers of hs-PDA. In the treatment group, there was a higher incidence of BPD (50.9% vs 33.3%) and mortality (18.2% vs 14%). These results align with previous trials that have found no benefit for pharmacological treatment, with the novel findings of possible harm and sex related differences, with males likely to benefit from expectant management by the primary composite outcome of death or NEC or BPD (absolute risk reduction of 30%). The authors speculate on a possible mechanism explaining the higher incidence of BPD after treatment, possibly by inhibition of vascular angiogenesis, based on a previous animal study showing that ibuprofen significantly suppresses retinal vascular growth. (4) However, it is currently unknown if ibuprofen suppresses pulmonary angiogenesis in premature infants. Fifty patients received a second ibuprofen course and seven patients received a third one and it might have been informative to evaluate if exposure to repeated doses increased the incidence or severity of BPD.

 

Four patients in the expectant management (EM) group experienced pulmonary hemorrhage versus one in the treatment group (RR 4.03 favoring treatment) and 11 patients developed IVH > grade 3 in the EM group versus 9 in the treatment group (RR 1.23 favoring treatment), complications known to be associated with PDA. (5–7) In the treatment group, 13 subjects developed pulmonary interstitial emphysema versus 5 in EM and 60 (versus 49 in EM) developed sepsis. The study was underpowered to determine whether these differences were statistically significant. A substantial proportion of subjects in both groups received acetaminophen and diuretics, with no clarification on dosage or duration. Finally, three (versus none in EM) subjects in the treatment group underwent surgical ligation.

 

This trial adds to the increasing evidence that the mere presence of the PDA should not be an indication for pharmacological treatment since not only it does not improve long term outcomes but might potentially be detrimental.

REFERENCES

1. Mitra S, Scrivens A, Kursell AM von, Disher T. Early treatment versus expectant management of hemodynamically significant patent ductus arteriosus for preterm infants. Cochrane Database Syst Rev [Internet]. 2020 [cited 2023 Jan 18];2020(12). Available from: https://www.readcube.com/articles/10.1002%2F14651858.cd013278.pub2

2. Clyman RI, Liebowitz M, Kaempf J, Erdeve O, Bulbul A, Håkansson S, et al. PDA-TOLERATE Trial: An Exploratory Randomized Controlled Trial of Treatment of Moderate-to-Large Patent Ductus Arteriosus at 1 Week of Age. J Pediatr. 2019 Feb;205:41-48.e6.

3. Rozé JC, Cambonie G, Le Thuaut A, Debillon T, Ligi I, Gascoin G, et al. Effect of Early Targeted Treatment of Ductus Arteriosus with Ibuprofen on Survival Without Cerebral Palsy at 2 Years in Infants with Extreme Prematurity: A Randomized Clinical Trial. J Pediatr. 2021 Jun;233:33-42.e2.

4. Beharry KDA, Modanlou HD, Hasan J, Gharraee Z, Abad-Santos P, Sills JH, et al. Comparative Effects of Early Postnatal Ibuprofen and Indomethacin on VEGF, IGF-I, and GH during Rat Ocular Development. Invest Ophthalmol Vis Sci. 2006 Jul 1;47(7):3036–43.

5. Garland J, Buck R, Weinberg M. Pulmonary hemorrhage risk in infants with a clinically diagnosed patent ductus arteriosus: a retrospective cohort study. Pediatrics. 1994 Nov;94(5):719–23.

6. Lewis MJ, McKeever PK, Rutty GN. Patent ductus arteriosus as a natural cause of pulmonary hemorrhage in infants: a medicolegal dilemma. Am J Forensic Med Pathol. 2004 Sep;25(3):200–4.

7. Khanafer-Larocque I, Soraisham A, Stritzke A, Al Awad E, Thomas S, Murthy P, et al. Intraventricular Hemorrhage: Risk Factors and Association With Patent Ductus Arteriosus Treatment in Extremely Preterm Neonates. Front Pediatr. 2019;7:408.