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Three Part Question

In [a preterm baby of gestational age less than or equal to 34 weeks] is [ibuprofen compared with indomethacin] equally efficacious at [treating echocardiographically proven patent ductus arteriosus and have fewer side effects]?

Clinical Scenario

A preterm baby of 28 weeks gestation with respiratory distress syndrome is admitted to the neonatal intensive care unit. On day 2 of life, the characteristic murmur or a patent ductus arteriosus (PDA) is heard, with the diagnosis confirmed by Doppler echocardiography. The attending neonatologist orders a course of indomethacin in an attempt to treat the PDA. The astute pediatric resident has just taken two tablets of ibuprofen to treat his post-call headache and wonders whether this alternative non-steroidal anti-inflammatory drug might be just as efficacious, with less side effects.

Search Strategy

Cochrane Library and PubMed
Cochrane: "ductus arteriosus patent" AND "indomethacin" AND "ibuprofen" (MeSH terms)
PubMed: "ductus arteriosus patent" AND "indomethacin" AND "ibuprofen" (MeSH terms) LIMIT to clinical trial

Search Outcome

Two systematic reviews, both irrelevant. Two protocols for a Cochrane review, one relevant. Nine clinical trials found, four of which were relevant.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Logo et al 2002	175 preterm neonates, GA	RCT (level 1b) Jadad score: 2	Echo proven closure of PDA	IBU=INDO for closure of PDA: ARR = 0.043 [95%CI -0.092 to 0.177]	Only echocardiographers were noted to be blinded Randomisation method not given Allocation concealment by sealed envelope
			Oliguria	INDO more likely to produce oliguria: p=0.017, NNH=7
			Post treatment serum creatinine	INDO resulted in higher post treatment creatinine (mean 89micromol/l, SD 24) than IBU (mean 81 micromol/l, SD 20): p=0.03
Van Overmeire et al 2000	148 preterm neonates, GA	RCT (level 1b) Jadad score: 2	Echo proven closure of PDA	IBU= INDO for closure of PDA: ARR = 0.041 [95%CI -0.109 - 0.19]	Only echocardiographers were noted to be blinded Randomisation method not given Allocation by concealment by sealed opaque envelope
			Oliguria	INDO more likely to produce oliguria: p= 0.03, NNH = 8
			Post treatment serum creatinine	INDO resulted in higher post-treatment creatinine: p=0.04
			Multiple logistic regression performed to determine predictors of oliguria	Independent predictors of oliguria were INDO treatment, high frequency ventilation, increased serum creatinine days 1-3, and lower ductul shunt velocity
Van Overmeire et al 1997	40 preterm neonates, GA	RCT (level 1b) Jadad score: 2	Echo proven closure of PDA	IBU = INDO for closure of PDA: ARR 0.05 [95%CI -0.208 to 0.308]	Randomisation method not given Allocation concealment by sealed envelope No blinding reported
			Oliguria	INDO more likely to produce oliguria: p = 0.02, NNH = 3
			Post-treatment serum creatinine	IBU = INDO for post-treatment serum creatinine: p=0.07
Supapannachart et al 2002	18 preterm infants (mean GA 30 weeks) with PDA based on clinical and xray criteria. Very ill babies excluded IBU (10mg/kg po od x 3 days) v INDO (0.2mg/kg po/iv q 12 h x 3 doses)	RCT (level 3b) Jadad score: 2	Clinical closure of PDA	IBU = INDO for closure of PDA: ARR 0.111 [95%CI -0.229 to 0.452]	Randomisation method not given Allocation concealment by sealed envelope No blinding reported INDO group was mixed between babies receiving and intravenous treatment No attempt at subset analysis
			Oliguria	NSD after day 1
			Post treatment serum creatinine	NSD

Comment(s)

All four studies were randomised controlled trials; however, the methods of randomisation were not reported. All used cards in sealed envelopes as the system of allocation concealment. Furthermore, there is no evidence that neonatologists, nurses or pharmacists were blinded in any study. Echocardiographers were blinded in two of the studies. Each study clearly shows the equivalence of ibuprofen and indomethacin in the treatment of patent ductus arteriosus. In addition, three studies showed a significant increase in oliguria among patients treated with intravenous indomethacin, and two studies showed a significant increase in serum creatinine. No study showed a difference in death, necrotising enterocolitis, or progression of intracranial haemorrhage between the two groups. All trials used a "high" dose of 0.2mg/kg every 12 hours for three days, as opposed to the "low" dose of 0.1mg/kg daily for six days. The recent Thai study attempts to compare oral ibuprofen with indomethacin; however, analysis is very difficult as patients in the indomethacin group received the drug by different routes of administration (some oral, some intravenous). Further trials with oral ibuprofen would be very helpful, especially for clinicians in countries were this is the only form of the drug available. Unfortunately, the intravenous preparation of ibuprofen is not easily available in North America.

Clinical Bottom Line

Intravenous ibuprofen is equivalent to intravenous indomethacin in the treatment of PDA in neonates. Patients receiving intravenous ibuprofen have a smaller rise in serum creatinine, and are less likely to develop oliguria (NNT = 6) than those receiving intravenous indomethacin.

References

1. Lago P, Bettiol T, Salvadori S et al. Safety and efficacy of ibuprofen versus indomethacin in preterm infants treated for patent ductus arteriosus: a randomised controlled trial. Eur J Pediatr 2002;161:202-207.
2. Van Overmeire B, Smets K, Lecoutere D et al. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. N Engl J Med 2000;343:674-81.
3. Van Overmeire B, Follens I, Hartmann S et al. Treatment of patent ductus arteriosus with ibuprofen. Arch Dis Child Fetal Neonatal Ed 1997;76:F179-84.
4. Supapannachart S, Limrungsikul A, Khowsathit P. Oral ibuprofen and indomethacin for treatment of patent ductus arteriosus in premature infants: a randomized trial at Ramathibodi Hospital. J Med Assoc Thai 2002;85(suppl 4):S1252-8.
5. Walia R, Ohlsson A. Ibuprofen for the treatment of a patent ductus arteriosus in preterm and/or low birth weight infants (Protocol for a Cochrane Review). In: The Cochrane Library, Issue 1. Oxford, 2003.