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EBNEO COMMENTARY: PATENT DUCTUS ARTERIOSUS (PDA)-TO TREAT EARLY OR NOT WITH IBUPROFEN?


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Rashida Javed and Harsha Gowda from UK review EbNeo January 2024 Article of the Month: Gupta S, Subhedar NV, Bell JL, et al. Trial of Selective Early Treatment of Patent Ductus Arteriosus with Ibuprofen. N Engl J Med. 2024;390(4):314-325. doi:10.1056/NEJMoa2305582. PMID: 38265644

READ HERE!

Hear it on the Journal Club of the Incubator Podcast!

Acta Commentary:

Acta Paediatrica - 2024 - Javed - EBNEO commentary Patent ductus arteriosus PDA To treat early or not with ibuprofen.pdf

Patent ductus arteriosus (PDA) is common in extreme preterm infants1, and its management is a subject of debate2. A large PDA of more than 1.5mm in diameter which is persistent beyond 3 days of age is associated with a higher mortality and morbidity as well as a greater risk of bronchopulmonary dysplasia3.

Systematic reviews of randomized, controlled trials showed that pharmacological treatment with ibuprofen induced PDA closure had no beneficial effects on clinical outcomes4,5. Therefore, the pharmacological treatment of PDA in extreme preterm infants has decreased6. However, the evidence to support this strategy is limited and contradictory7.

In the Baby-OSCAR trial, preterm infants between 23+0 weeks to 28+6 weeks, death or moderate or severe bronchopulmonary dysplasia assessed at 36 weeks of postmenstrual age occurred in 69.2% (220/318) infants in the ibuprofen group and 63.5% (202/318) in the placebo group (adjusted risk ratio 1.09, 95% CI 0.98-1.20). This was statistically not significant. Subgroup analysis of primary outcome for each gestational age favors placebo group but none were statistically significant as numbers were small. Secondary outcomes like intraventricular hemorrhage, cystic periventricular leukomalacia, clinically significant pulmonary hemorrhage, and discharge on home oxygen were higher in ibuprofen group but none of them were statistically significant.

PDA closed or less than 1.5mm in diameter at 3 weeks of age confirmed by echocardiography was 55.5% (176/317) in the ibuprofen group compared to 37% (117/316) in the placebo group (adjusted risk ratio, 1.50; 95% CI, 1.30 to 1.74). Open-label treatment including surgical ligation was 14.2% in the ibuprofen group and 29.8% in the placebo group. Even though in the ibuprofen group, more PDA closed or less than 1.5mm in diameter at 3 weeks of age, no improvement in the primary outcome was observed.

The limitations of the trial were, not meeting the enrolment goal of 730 infants because of non-availability of drugs, changes in the clinical practice and effect of COVID-19 pandemic. Although early assessment for randomization was encouraged, first dose of ibuprofen or a placebo was administered at a median of 61 hours after birth. This trial did not target hemodynamically significant PDA identified by clinical findings, rather than those screened by echocardiography. Other important limitation was, in spite of strict criteria, open-label therapy was received in 29.8% in the placebo group which made it more difficult to identify between-group differences in clinical outcomes.

Despite above limitations, the baby OSCAR trial is the largest study on early pharmacological treatment of PDA using strict echocardiography screening criteria to diagnose hemodynamically significant PDA. Recently published Beneductus trial in similar gestational age group and comparable primary and secondary outcomes as the baby OSCAR trial showed expected management of PDA noninferior to early management with ibuprofen8. Cochrane reviews published in 2020 on ibuprofen as a prevention of PDA and treatment of PDA concluded that ibuprofen closes PDA but did not benefit short term or long-term outcomes9.

To conclude, in extreme preterm infants with large PDA, there is no evidence that early treatment with ibuprofen would reduce the risk of death or moderate or severe BPD at 36 weeks postmenstrual age. It is plausible that an attempt to close the PDA with ibuprofen may be more harmful than the condition itself. Ibuprofen has potential adverse effects and there are no proven clinical benefits. So, clinicians should avoid using it for early treatment of PDA.

References:

Lee JA, Kim M-J, Oh S, Choi BM. Current status of therapeutic strategies for patent ductus arteriosus in very-low-birthweight infants in Korea. J Korean Med Sci 2015; 30: Suppl 1: S59-S66.

Benitz WE. Treatment of persistent patent ductus arteriosus in preterm infants: time to accept the null hypothesis? J Perinatol 2010; 30: 241-52.

Sellmer A, Bjerre JV, Schmidt MR, et al. Morbidity and mortality in preterm neonates with patent ductus arteriosus on day 3. Arch Dis Child Fetal Neonatal Ed 2013; 98: F505-F510.

Jansen EJS, Hundscheid T, Onland W, Kooi EMW, Andriessen P, de Boode WP. Factors associated with benefit of treatment of patent ductus arteriosus in preterm infants: a systematic review and meta-analysis. Front Pediatr 2021; 9: 626262.

Mitra S, Florez ID, Tamayo ME, et al. Association of placebo, indomethacin, ibuprofen, and acetaminophen with closure of hemodynamically significant patent ductus arteriosus in preterm infants: a systematic review and meta-analysis. JAMA 2018; 319: 1221-38.

Ngo S, Profit J, Gould JB, Lee HC. Trends in patent ductus arteriosus diagnosis and management for very low birth weight infants. Pediatrics 2017; 139(4): e20162390.

Hundscheid T, Jansen EJS, Onland W, Kooi EMW, Andriessen P, de Boode WP. 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. Front Pediatr 2021; 9: 626261.

Hundscheid T, Onland W, Kooi EMW, et al. Expectant Management or Early Ibuprofen for Patent Ductus Arteriosus. N Engl J Med. 2023;388(11):980-990. doi:10.1056/NEJMoa2207418

Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants. Cochrane Database Syst Rev. 2020;2(2):CD003481. Published 2020 Feb 11.

 

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  • 2 weeks later...

Many authors don’t use a Boolean logic when approaching PDA. A Pediatric cardiologist can treat an hemodynamic significant VSD left right, so why can’t I treat a HSPDA? However other authors think differently.( McNamara P., El Khuffash A.,Etc ) Very interesting “Patent Ductus Arteriosus and Bronchopulmonary Dysplasia -Associated Pulmonary Hypertension. A Bayesian Meta-Analysis.” (Jama 2023) ;”Pulmonary Hypertension in established Bronchopulmonary Dysplasia”. ( page 201 , specially)( Clin. Perinatology 2024 Lakshminrusimha S.)… pda is a conundrum because we haven’t proven yet the theorem (need of Rct) but I think there’s a clinic logic… 

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