Endothelin receptor antagonists for persistent pulmonary hypertension in term and late preterm infants

Endothelin, a powerful vasoconstrictor, is one of the mediators in the causation of persistent pulmonary hypertension of the newborn (PPHN). Theoretically, endothelin receptor antagonists (ETRA) have the potential to improve the outcomes of infants with PPHN.

To assess the efficacy and safety of ETRA in the treatment of PPHN in full-term, post-term and late preterm infants.To assess the efficacy and safety of selective ETRAs (which block only the ETA receptors) and non-selective ETRAs (which block both ETA and ETB receptors) separately.

CENTRAL (Cochrane Central Register of Controlled Trials), MEDLINE, EMBASE and CINAHL databases were searched until December 2015.

Randomised, cluster-randomised or quasi-randomised controlled trials were eligible.

Two review authors independently searched the literature, selected the studies, assessed the risk of bias and extracted the data. A fixed-effect model was used for meta-analysis. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence.

Two randomised controlled trials of ETRA met the inclusion criteria. Both studies utilized oral Bosentan. The first study was done in a setting where inhaled nitric oxide (iNO) therapy was not available. Forty-seven infants (≥ 34 weeks' gestation) were randomised to receive either Bosentan or placebo. The second study was a multicentre study where iNO therapy was the standard of care for PPHN. Twenty-one infants were randomised to receive either 'iNO plus Bosentan' or 'iNO plus placebo'.In the first study, there was no significant difference in the incidence of death before hospital discharge between the Bosentan and placebo groups (1/23 vs 3/14; RR 0.20, 95% CI 0.02 to 1.77; RD -0.17, 95% CI -0.40 to 0.06). A higher proportion of infants in the Bosentan group showed improvement in oxygenation index (OI) at the end of therapy (21/24 vs 3/15; RR 4.38, 95% CI 1.57 to 12.17; RD 0.68, 95% CI 0.43 to 0.92; number needed to treat for a beneficial outcome (NNTB) 1.5). The duration of mechanical ventilation was lower in the Bosentan group (4.3 ± 0.9 vs 11.5 ± 0.6 days; MD -7.20, 95% CI -7.64 to -6.76). There was no significant difference in adverse neurological outcomes at six months (0/23 vs 4/14; RR 0.07, 95% CI 0.00 to 1.20; RD -0.29, 95% CI -0.52 to -0.05). The study suffered from a high risk of attrition bias since 8/23 infants in the placebo group were excluded from various analyses. Since the protocol for the study could not be accessed, the study suffered from unclear risk of reporting bias.In the second study, there was no significant difference in the incidence of treatment failure needing extracorporeal membrane oxygenation (ECMO) between the 'iNO plus Bosentan' vs 'iNO plus placebo' groups (1/13 vs 0/8; RR 1.93, 95% CI 0.09 to 42.35; RD 0.08, 95% CI -0.14 to 0.30). There was no significant difference in the median time to wean from iNO ('iNO plus Bosentan': 3.7 days (95% CI 1.17 to 6.95); 'iNO plus placebo': 2.9 days (95% CI 1.26 to 4.23); P = 0.34). There were no significant differences in the OI 0, 3, 5, 12, 24, 48 and 72 hours of treatment between the groups. There were no significant differences in the time to complete weaning from mechanical ventilation (median 10.8 days (CI 3.21 to 12.21) versus 8.6 days (CI 3.71 to 9.66); P = 0.24). The study had unequal distribution to the Bosentan group (N = 13) and the placebo group (N = 8). The methods used for generating random sequence numbers and allocation concealment were unclear, resulting in unclear risk of selection bias.Both studies reported that Bosentan was well tolerated and no major adverse effects were noted. Data from the two studies was not pooled given the heterogenous nature of the clinical settings and the modalities used for the treatment of PPHN.Overall, the quality of evidence was considered low, given the small sample size of the included studies, the numerical imbalance between the groups due to randomisation and attrition, and unclear risk of bias on some of the important domains.

There is inadequate evidence to support the use of ETRAs either as stand-alone therapy or as adjuvant to inhaled nitric oxide in PPHN. Adequately powered RCTs are needed.