MANUSCRIPT CITATION

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

Reviewed By

Dr. Rashida Javed(1),
Dr. Harsha Gowda(2)

(1) Neonatal intensive care unit, University Hospitals Leicester, Leicester, UK
(2) Neonatal intensive care unit, University Hospitals Birmingham, Birmingham, UK

Corresponding author: R Javed, Neonatal intensive care unit, Leicester Royal Infirmary Hospital, LE1 5WW, UK.
Email: rashida.javed@nhs.net

TYPE OF INVESTIGATION

Treatment

QUESTION

In extreme preterm infants less than 28-week gestation (P) who receive ibuprofen for large PDA after birth (I) compared to the infants receiving placebo (C) reduces the mortality or moderate or severe bronchopulmonary dysplasia(O) at 36 weeks of postmenstrual age (T)?

METHODS

Design: Multicentre randomised control trial

Allocation: Infants were randomly assigned to probabilistic minimization algorithm and assigned patients in a 1:1 ratio to one of the two group to ensure balance with respect to the size of the PDA, gestational age at birth, age, sex, trial site, whether the infant was from a multiple birth, mode of respiratory support, and whether inotropes were received. Infants in multiple births underwent randomization individually.

Blinding: Double blinded, placebo-controlled trial

Follow up period: Primary outcomes till 36 weeks of postmenstrual age and secondary outcomes till discharge from the neonatal unit.

Setting: 32 neonatal intensive care units in the United Kingdom

Patients: 653 patients were randomised in the study (22 during internal pilot phase and 631 in main recruitment phase). 326 infants were assigned to receive ibuprofen and 327 to receive placebo.

Inclusion criteria:

• Infants born between 23⁺⁰ days and 28⁺⁶ days gestation.
• Less than 72 hours old
• Confirmed by echocardiography to have a large PDA which is at least 1.5 mm in diameter (determined by gain optimised colour Doppler)
• Has unrestrictive pulsatile (left to right) flow (ratio of flow velocity in PDA Maximum (Vmax) to Minimum (Vmin) > 2:1)) or, growing flow pattern (< 30% right to left)
• The responsible clinician is uncertain about whether the baby might benefit from treatment to close the PDA
• Written informed consent is obtained from the parent(s)

Exclusion criteria:

• Infants with clinical concerns for acute pulmonary hypertension
• No realistic prospect of survival
• Severe congenital anomaly
• Clinical or echocardiography suspicion of congenital structural heart disease that contraindicates treatment with ibuprofen
• Other conditions that would contraindicate the use of ibuprofen (active bleeding especially intracranial or gastrointestinal bleeding, coagulopathy, thrombocytopenia (platelet count < 50,000), renal failure, life threatening infection, pulmonary hypertension, known or suspected necrotising enterocolitis (NEC))
• Administration of Indomethacin, ibuprofen, or paracetamol after birth.

Echocardiography: Echocardiography was performed within 72 hours of birth to assess the eligibility and at 3 weeks of age to assess the patency of PDA while minimising open-label treatment. A sample of echocardiograms from 65 infants was reviewed independently by a paediatric echocardiographer who was unaware of the treatment assignments.

Intervention: Ibuprofen sodium vs matched placebo (0.9% sodium chloride). Ibuprofen was administered parenterally as loading dose of 10mg/kg, followed by two doses of 5mg/kg at least 24 hours apart. Placebo was given as first dose of 2ml/kg, followed by two doses of 1ml/kg 24 hours apart. Only one course of ibuprofen and placebo were given.

Prespecified criteria for open-label medical and surgical treatment was used. Clinical criteria included: Inability to wean on ventilator (ventilated for at least 7 days continuously) and any of the following: Inability to wean oxygen, or Persistent hypotension, or Pulmonary hemorrhage, or Signs of cardiac failure, and Echocardiographic criteria included: Presence of a large PDA with a ductal dimension of ≥2.0 mm and unrestrictive pulsatile left to right flow in PDA and presence of a hyperdynamic circulation or ductal steal.

Outcomes:

Primary outcome:

Death or moderate or severe bronchopulmonary dysplasia assessed at 36 weeks of postmenstrual age.

Secondary outcomes:

• Severity of bronchopulmonary dysplasia
• Severe intraventricular hemorrhage
• Cystic periventricular leukomalacia
• Retinopathy of prematurity requiring treatment
• Clinically significant pulmonary hemorrhage
• Acute pulmonary hypertension
• Definitive necrotizing enterocolitis
• Closed or clinically non-significant PDA less than 1.5 mm in diameter with restricted flow confirmed by echocardiography at 3 weeks age
• Open-label treatment of a symptomatic PDA by surgical treatment
• Weight gain: a change in z score between birth and discharge (or death if sooner)
• Discharge home on supplemental oxygen

Analysis and Sample size:

The incidence of primary outcome was predicted to be 60% in the placebo group. A sample of 730 infants was calculated to be required in order to detect a clinically important absolute risk reduction of 12% points (an incidence of 60% in the placebo group and an incidence of 48% in the ibuprofen group) with 90% power and a type 1 error of 5% under the assumption that 1% of infants would be lost to follow-up.

Analyses was performed according to the intention-to-treat principle, with infants excluding from the analysis only if their data were missing. Analyses were adjusted for minimization factors, such as the size of the PDA at randomization, gestational age at birth, age at randomization, sex, whether the infant was from a multiple birth, mode of respiratory support at randomization, whether inotropes were received at the time of randomization, and trial site, as well as for the correlation between siblings from multiple births, when technically possible.

Binary outcomes were analyzed by means of mixed-effects. Poisson regression with a robust variance estimator; risk ratios and 95% confidence intervals are reported. Continuous outcomes were analyzed with the use of linear regression models; mean differences and 95% confidence intervals (after checking model assumptions) were reported.

Patient follow up: Primary outcome assessment was carried out in 318 infants in both the groups due to missing data, withdrawal of parental consent and not receiving the assigned medication.

Main results:

Maternal and infant baseline characteristics were well balanced between the groups for gestational age, birth weight, sex, ethnicity, postnatal age at randomization, mode of delivery, Apgar score 5 min after birth, median PDA diameter, mode of respiratory support and receipt of inotropes.

Primary outcome: A primary-outcome event (death or moderate or severe bronchopulmonary dysplasia assessed at 36 weeks of postmenstrual age) occurred in 220 of 318 infants (69.2%) in ibuprofen group and 202 of 318 infants (63.5%) in placebo group. (adjusted risk ratio, 1.09; 95% CI, 0.98 to 1.20; P = 0.10). (Table 1)

Secondary outcome: There was no significant between-group difference in the rate of secondary and adverse events. (Table 2)

Table 1:

Primary outcomes
	Ibuprofen (N= 324)	Placebo (N=322)	Adjusted Risk Ratio (95% CI)
Death or moderate or severe bronchopulmonary dysplasia assessed at 36 wk of postmenstrual age	220/318 (69.2%)	202/318 (63.5%)	1.09 (0.98- 1.20%)
Subgroup analyses	No. of events/ total no. (%)
Gestational age at birth
23 to 23+6 days	28/29 (97)	29/29 (100)	0.97 (0.94- 1.01)
24 to 24+6 days	53/59 (90)	51/58 (88)	1.02 (0.91- 1.14)
25 to 25+6 days	46/64 (72)	44/63 (70)	1.03 (0.81- 1.30)
26 to 26+6 days	40/65 (62)	35/66 (53)	1.17 (0.85- 1.62)
27 to 27+6 days	34/59 (58)	22/54 (41)	1.35 (0.89- 2.05)
28 to 28+6 days	19/42 (45)	21/48 (44)	1.06 (0.67- 1.68)
Size of PDA at randomization
1.5 to <2.0 mm	58/83 (70)	50/81 (62)	1.14 (0.94- 1.37)
2.0  to <3.0 mm	131/196 (67)	127/198 (64)	1.03 (0.91- 1.17)
>3.0 mm	31/39 (79)	25/39 (64)	1.25 (0.97- 1.62)
Mode of respiratory support at randomization
Invasive ventilation	164/205 (80)	155/202 (77)	1.04 (0.95- 1.14)
Noninvasive ventilation or no support	56/113 (50)	47/116 (41)	1.24 (0.89- 1.72)
Overall	220/318 (69)	202/318 (64)	1.09 (0.98- 1.20)

Table 2:

Secondary outcomes
	Ibuprofen (N= 324)	Placebo (N=322)	Adjusted Risk Ratio (95% CI)
Death by 36 wk of postmenstrual age	44/323 (13.6%)	33/321 (10.3%)	1.32 (0.92–1.90)
Survival to 36 wk of postmenstrual age- no. of infants	280	289	—
Moderate or severe bronchopulmonary dysplasia at 36 wk of postmenstrual age	176/274 (64.2%)	169/285 (59.3%)	1.09 (0.96–1.23)
Any intraventricular hemorrhage	137 (42.3%)	132 (41.0%)	—
Grade I or II without ventricular dilatation	92 (28.4%)	98 (30.4%)	—
Grade III or IV with ventricular dilatation or intraparenchymal abnormality	45 (13.9%)	34 (10.6%)	1.30 (0.93–1.82)
Cystic periventricular leukomalacia	15 (4.6%)	9 (2.8%)	1.62 (0.69–3.83)
Treatment for retinopathy of prematurity in at least one eye	45 (13.9%)	45 (14.0%)	0.98 (0.68–1.42)
Clinically significant pulmonary hemorrhage	24/322 (7.5%)	18/322 (5.6%)	1.39 (0.70–2.77)
Treatment for acute pulmonary hypertension with pulmonary vasodilator	17 (5.2%)	16 (5.0%)	1.04 (0.51–2.13)
Severe necrotizing enterocolitis	41/323 (12.7%)	41/322 (12.7%)	1.01 (0.67–1.51)
PDA closed or <1.5 mm at 3 wk of age, confirmed by echocardiography	176/317 (55.5%)	117/316 (37%)	1.50 (1.30–1.74)
PDA ≥1.5 mm at 3 wk of age, not treated medically or by surgical closure	74/321 (23.1%)	109/317 (34.4%)	0.67 (0.53–0.85)
Open-label surgical treatment of a symptomatic PDA	9 (2.8%)	31 (9.6%)	0.29 (0.18–0.47)
Discharged home with supplemental oxygen	130 (41.3%)	123 (39.2%)	1.06 (0.92–1.22)
Weight gain
No. of infants with data	257	265	—-
Mean change in z score between birth and discharge	-1.0 ± 1.0	-1.0 ± 1.0	0.1 (−0.1 to 0.2)

 

 

Conclusion:

The risk of death or moderate or severe bronchopulmonary dysplasia at 36 weeks of postmenstrual age was not significantly lower among infants who received early treatment with the ibuprofen than among those who received placebo.

Commentary:

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 outcomes^4,5. 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:

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2. Benitz WE. Treatment of persistent patent ductus arteriosus in preterm infants: time to accept the null hypothesis? J Perinatol 2010; 30: 241-52.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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
9. 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.