EBNEO Posted May 6 Share Posted May 6 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. Link to comment Share on other sites More sharing options...
criscuolo Posted May 17 Share Posted May 17 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… 1 Link to comment Share on other sites More sharing options...
criscuolo Posted May 17 Share Posted May 17 In addition… El k..pdf Link to comment Share on other sites More sharing options...
vinayakneo Posted May 28 Share Posted May 28 The biggest problem with BeNeDuctus and Baby Oscar is the patient selection. The hemodynamically significant PDA definition based on PDA characteristics alone (Diameter > 1.5 mm and flow characteristics) may have high sensitivity but poor specificity. Various PDA scores are available which are better at defining the HSPDA than PDA characteristics alone. Interestingly they had more echo-based criteria before open-label use than they used to define HSPDA. I wonder why they did not use those in the first place. It implies that they may have treated some non-HSPDAs with Ibuprofen when it was not needed. No matter how well their trial was designed after patient selection, the trial outcomes might not be true due to selection bias. EBNEO commentary authors have not covered this part. In addition just like CLD, there has been a significant shift in HSPDA over the past 2 decades. HSPDA is a major issue in < 26 weeks infants and most of the 27 or 28 weeks infants can close their PDAs very well on their own without significant intervention. They rarely exhibit significant CLD purely from HSPDAs which was one of the main primary outcomes in both trials. In both BeNeDuctus and Baby Oscar trials, 50% of the patients were > 26 weeks at birth. (In BeNeDuctus infants < 26 weeks were 64/136 in the Ibuprofen group vs 55/137 in the expectant group and in BabyOscar had 118/324 in ibuprofen vs 125/322 in the expectant group). Also, 30% open use of Ibuprofen in the control arm alters the outcomes of the trial significantly. My take is that these trials show us that the current medical management (Ibuprofen) for PDA may be suboptimal and we have to look at better ways of treating it. A trial of PDA treatment with catheter-guided device closure (Picolo) against a placebo may answer this question. Due to the 50-60% efficacy of NSAIDs, it will be hard to recruit many patients within 1st week of life. It will be a herculean task to get consent from families and convince physicians to do catheter ligation as the first intervention for HSPDA. Till then, we will continue to debate 'how to treat PDAs' for the next few decades. 1 Link to comment Share on other sites More sharing options...
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