Comparison of efficacy and safety of oral ibuprofen versus oral indomethacin

Abstract

We read the article by Khuwuthyakorn et al. [1] which compared the efficacy of oral ibuprofen and oral indomethacin in very low-birthweight (VLBW) infants. The conclusions drawn in this underpowered trial contradict existing evidence and cannot be generalised. We would like to highlight some issues. The authors relied more on clinical features to detect and treat haemodynamically significant patent ductus arteriosus (PDA) rather than undertaking screening echocardiography. In very and extremely low-birthweight infants, the clinical signs alone have low sensitivity (30–40%) and poor predictive value (60%). Also, the clinical signs will lead to a 1–4-day delay in diagnosis [2]. Furthermore, the authors used only two echocardiographic parameters which might not be optimal in diagnosing hsPDA in this population. A detailed early echocardiogram involving multiple parameters (ductal velocity, antegrade pulmonary artery diastolic flow, E wave/A wave ratio, isovolumetric relaxation time and retrograde diastolic flow in the aorta) would be more sensitive and useful. According to the current literature, PDA closure rates in the ibuprofen group are very low. A recent network meta-analysis [3] has demonstrated that highdose ibuprofen has the highest PDA closure rates. The oral ibuprofen was found to be superior to the oral indomethacin, and the failure rates were significantly less than reported in this study. So the results of this study cannot be generalised. The authors did not compare sepsis and platelet count between the two groups. Sepsis and low platelet count are independent predictors of delayed closure and treatment failure in PDA [4]. The higher rates might be owing to more sepsis in the oral ibuprofen group. It would be worthwhile comparing these variables. Compared with other studies, the PDA ligation rates are extremely high [5]. One of the reasons for such high rates may be no orminimal use of the intravenous route to administer non-steroidal anti-inflammatory drugs (indomethacin, ibuprofen and paracetamol). Recent evidence shows that paracetamol is as effective as other therapies and remains a good alternative therapeutic agent when ibuprofen and indomethacin are contraindicated. Combined therapy may be a useful alternative for monotherapy-resistant hsPDA in preterm neonates. Therefore, combination therapy remains a good option before considering surgical ligation. The authors should compare the oral ibuprofen and indomethacin groups for the number of neonates needing a repeat course of the drug. The proportions of infants developing bronchopulmonary dysplasia, requiring surgery for retinopathy of prematurity, and abnormal oto-acoustic emissions are quite high compared with previous studies. We agree with the authors’ conclusion that the higher doses of ibuprofen will result in better closure rates. Future studies can investigate this but caution is required because the higher dosage is likely to cause more adverse gastrointestinal and renal effects. Although the study was appropriately designed for the relevant clinical outcomes, the points mentioned above question the generalisability of the study. The small sample size may be responsible for the skewed results. Hence, an adequately powered trial with a sufficient sample size should be considered.