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

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Authors

Kiran More1, 2, Gayatri K Athalye-Jape3, Shripada C Rao4, Sanjay K Patole5

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


1Department of Neonatology, Christchurch Women's Hospital, Canterbury, New Zealand [top]
2University of Otago, Dunedin, New Zealand [top]
3Department of Neonatology, Princess Margaret Hospital and King Edward Hospital, Subiaco, Australia [top]
4Centre for Neonatal Research and Education, King Edward Memorial Hospital for Women and Princess Margaret Hospital for Children, Perth, Western Australia, Australia [top]
5School of Paediatrics and Child Health, School of Women's and Infant's Health, University of Western Australia, King Edward Memorial Hospital, Perth, Australia [top]

Citation example: More K, Athalye-Jape GK, Rao SC, Patole SK. Endothelin receptor antagonists for persistent pulmonary hypertension in term and late preterm infants. Cochrane Database of Systematic Reviews 2016, Issue 8. Art. No.: CD010531. DOI: 10.1002/14651858.CD010531.pub2.

Contact person

Kiran More

Department of Neonatology
Christchurch Women's Hospital
Canterbury
New Zealand

E-mail: drkiranmore@yahoo.com

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Dates

Assessed as Up-to-date: 28 December 2015
Date of Search: 10 December 2015
Next Stage Expected: 31 December 2018
Protocol First Published: Issue 5, 2013
Review First Published: Issue 8, 2016
Last Citation Issue: Issue 8, 2016

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Abstract

Background

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.

Objectives

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.

Search methods

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

Selection criteria

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

Data collection and analysis

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.

Main results

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 (greater than/or equal to 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.

Authors' conclusions

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.

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Plain language summary

Endothelin receptor antagonists for persistent pulmonary arterial hypertension

 

Background: Some newborn babies develop abnormally high blood pressure in the arteries of the lung. This condition is called persistent pulmonary hypertension of the newborn (PPHN). Babies with PPHN present with breathing difficulties and low oxygen levels.Traditionally such babies are managed with respirators and administration of a special gas called nitric oxide. In many cases, babies do not improve in spite of these measures. A new class of drugs called endothelin receptor antagonists are being tested for PPHN.

Method: We systematically reviewed the medical literature through December 2015 to gather current evidence on the use of this class of drugs in newborn babies.

Results: We found very limited data from two included studies for the use of this class of drugs in newborn babies. Overall, the quality of evidence was considered low because of the very small sample size and methodological issues in the included studies.

Conclusion: More research is needed to find out if endothelin receptor antagonists are useful in newborn babies with PPHN. At present the use of these medications for this condition can not be recommended.

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Background

Description of the condition

Persistent pulmonary hypertension of the newborn (PPHN)

Persistent pulmonary hypertension of the newborn (PPHN) or persistent fetal circulation (PFC) is a clinical syndrome characterised by failure of the lung circulation to achieve or sustain the normal drop in pulmonary vascular resistance (PVR) at birth (Gersony 1984)(Konduri 2009). The incidence of PPHN is estimated at two per 1000 live births and is associated with substantial morbidity and mortality (Steinhorn 2010).

During fetal life, low oxygen tension and high levels of endogenous vasoconstrictors (endothelin-1 and thromboxane) facilitate the maintenance of high PVR (Lakshminrusimha 1999). A dramatic decrease in PVR occurs immediately after birth as lungs take over the gas exchange function. Several mechanisms contribute to the normal fall in PVR at birth, including increased oxygen tension, ventilation and shear stress. These physiological stimuli lower the PVR through increased release of potent endogenous vasodilators such as nitric oxide (NO) and prostacyclin (PGI2), and decreased activity of vasoconstrictors such as endothelin (ET-1) (Levy 2005a; Levy 2005b). Neonates failing to achieve the normal decrease in PVR at birth develop PPHN (Rao 2010).

Echocardiography is an important tool in the diagnosis of PPHN. The main findings are presence of right to left shunting at the atrial level or via the patent ductus arteriosus, near or supra-systemic pulmonary pressures and the presence of tricuspid regurgitation (Rao 2010; Stayer 2010; Dhillon 2012).

Management of PPHN includes prevention or treatment of pulmonary vasoconstriction, support of right-ventricle function, treatment of the underlying disease and promotion of regressive remodelling of structural pulmonary vascular changes (Oishi 2011). The vital role of nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signalling in the regulation of the perinatal lung circulation, leading to the development and successful application of inhaled nitric oxide (iNO) therapy for PPHN, is now well established (Abman 2007). However, approximately 40% of recipients will not respond to iNO (Steinhorn 2010); and hence newer alternatives or adjuncts to iNO are being explored.

Description of the intervention

Endothelin receptor antagonists (ETRAs)

Endothelin-1 was discovered by Japanese scientists Yanagisawa and co-workers (Yanagisawa 1988), who described it as one of the most potent vasoconstrictors. It was subsequently characterised as the most potent vasoconstrictor ever identified, being 100 times more potent than noradrenaline (Barton 2008). Endothelins are a family of 21 aminoacid peptides that are secreted mainly by the systemic and pulmonary vascular endothelial cells. There are three isoforms, ET-1, ET-2 and ET-3, of which ET-1 is biologically the most active. ET-1 is produced in response to various stimuli such as hypoxia, hyperoxia, reactive oxygen species, cytokines, catecholamine stress etc. (Abman 2009). It is synthesised from its biologically inactive precursor by the endothelin-converting enzyme (Davenport 2006). ET-1 is also a smooth muscle mutagen (Abman 2009; Galiè 2004).

ET-1 acts via two G protein coupled receptors: ETA receptors, which are located primarily on the vascular smooth muscle cells; and ETB receptors, which are expressed both on vascular endothelium and vascular smooth muscle cells. They are present in both pulmonary as well as systemic vasculature. The activation of ETA receptors mediates vasoconstriction, smooth muscle proliferation, hypertrophy, cell migration and fibrosis. The activation of ETB receptors stimulates the release of potent vasodilators (NO and PGI2), which also exhibit antiproliferative properties and prevent apoptosis (La 1995; Dakshinamurti 2005; Abman 2009; Rao 2010).

ET-1 plays an important role in the pathogenesis of pulmonary arterial hypertension in adult and pediatric populations. In a very important study in this field, Giaid and co-workers found increased expression of endothelin-1 in vascular endothelial cells of adults with pulmonary hypertension (Giaid 1993). Plasma ET-1 levels are known to be elevated in adults and children with pulmonary hypertension and correlate with increased morbidity and mortality (Allen 1993; Shao 2011).

ET-1 is also known to play an important role in the pathogenesis of PPHN in newborn infants. During fetal life, ET-1 and its receptors are strongly expressed in the pulmonary circulation early during lung development. Basal ET-1 activity contributes to the high pulmonary vascular resistance in utero (Abman 2009), via predominant action on the ETA receptors. Activation of the ETB receptor causes vasodilatation by release of nitric oxide and partly contributes to pulmonary vasodilatation that occurs at birth. In PPHN, the balance is in favour of ETA receptor activation leading to increased pulmonary vascular resistance. In a case control study, (Rosenberg 1993 found that plasma ET-1 concentrations were significantly higher in neonates with PPHN compared to those with hyaline membrane disease or healthy newborn infants. They also reported that plasma ET-1 levels correlated with disease severity in PPHN. In another case control study, Endo and co-workers also found that plasma ET-1 concentrations were significantly higher in PPHN than in the control group at less than 12 hours and 24 hours of age (Endo 2001). de Lagausie and co-workers studied the ETA and ETB receptor protein expression using immunohistochemistry in 10 lung specimens obtained from newborn infants with congenital diaphragmatic hernia (CDH) and four normal lung specimens (de Lagausie 2005). In the lungs of neonates with CDH, immunohistochemistry of both ETA and ETB receptors demonstrated over-expression in the thickened media of pulmonary arteries. Higher levels of ETA and ETB mRNA were found in CDH pulmonary arteries than in controls: this increase was more pronounced for ETA mRNA. They concluded that dysregulation of ET-1 receptors may contribute to PPHN associated with CDH (de Lagausie 2005).

Given the role of endothelins in PPHN, blocking the ET receptors using endothelin receptor antagonists (ETRAs) may be of benefit in the treatment of PPHN. Bosentan and Tezosentan are non-selective ETRAs because they block both ETA and ETB receptors, whereas Sitaxentan and Ambrisentan are selective ETA receptor inhibitors (Luscher 2000; Geiger 2006; O'Callaghan 2011). The ETRAs are administered either orally or intravenously (Torre-Amione 2003). The inhalation route has also been tried in animal models of pulmonary hypertension (Persson 2009).

How the intervention might work

The biology of ET receptors is complex and incompletely understood (Abman 2009). ETRAs appear to work by blocking the endothelin receptors thereby leading to decreased pulmonary vascular resistance and decreased medial hypertrophy of pulmonary vasculature. Newborn animal studies have shown that ETRAs reduce pulmonary hypertension secondary to sepsis (Peng 2003) and meconium aspiration syndrome (Kuo 2001). Ambalavanan and co-workers studied hypoxia-induced pulmonary vascular remodeling (HPVR) leading to PPHN or cor pulmonale in a newborn mouse model. They demonstrated that HPVR secondary to chronic hypoxia can be completely prevented and partially reversed by ETA blockade (Ambalavanan 2005).

The most important potential adverse effect of ETRA is hypotension because ETRAs block the endothelin receptors not only in the pulmonary circulation, but also in the systemic circulation. Other potential adverse effects are liver dysfunction, cardiac arrhythmias and hypoxaemia. However, a systematic review of observational studies of Bosentan in a paediatric population concluded that it is a well tolerated and effective therapy for paediatric pulmonary hypertension (Beghetti 2009).  

Why it is important to do this review

The current treatment for PPHN involves conventional/high-frequency ventilation, administration of oxygen, sedation, iNO and the phosphodiesterase 5 (PDE) inhibitor, Sildenafil (Rao 2010; Shah 2011). Approximately 40% of infants do not respond or will not sustain a response to iNO (Steinhorn 2010); iNO is also very expensive. Hence, evaluation of alternatives to iNO in the management of PPHN are urgently needed.

Experience with the use of ETRA in adults with pulmonary arterial hypertension

A recently published Cochrane review in adults with pulmonary hypertension included 12 randomised controlled trials involving 1471 participants (Liu 2013). They concluded that ETRAs can increase exercise capacity, improve World Health Organization (WHO)/New York Heart Association (NYHA) functional class, prevent WHO/NYHA functional class deterioration, reduce dyspnoea and improve cardiopulmonary haemodynamic variables in such individuals (Liu 2013).

Experience with the use of ETRA in children with pulmonary arterial hypertension

Observational studies have shown that ETRAs may improve the outcomes of children with pulmonary hypertension associated with congenital heart disease (Nemoto 2007; Goissen 2008; Hirono 2010), congenital diaphragmatic hernia (Stathopoulos 2011) and bronchopulmonary dysplasia (Krishnan 2008). A systematic review of observational studies also suggested a beneficial effect of ETRA in paediatric pulmonary hypertension (Beghetti 2009).

Experience with the use of ETRA in animal models of PPHN

Tezosentan has been shown to improve survival and decrease pulmonary artery pressure in a porcine model of acute pulmonary arterial hypertension after meconium aspiration (Geiger 2006; Geiger 2008).

Pearl and co-workers showed that Bosentan prevents hypoxia-reoxygenation-induced pulmonary hypertension and improves pulmonary function in neonatal piglets (Pearl 1999).

Clinical experience with the use of ETRA in neonatal population

Clinical experience with ET-1 receptor antagonists in the neonatal population is limited. Nakwan 2009 reported the benefits of Bosentan in a neonate with PPHN. Radicioni and co-workers reported the use of oral Bosentan as adjunct therapy to iNO and oral Sildenafil in a preterm infant with PPHN after preterm rupture of membranes (PPROM) (Radicioni 2011). Goissen 2008 also reported the benefits of Bosentan in PPHN associated with congenital heart disease.

Drinker 2012 reported on the use of Bosentan in four preterm infants with CLD and pulmonary hypertension (gestational age: 23, 24, 25, and 32 weeks). The median age at commencement of Bosentan was 208 days. Three participants died subsequently. They concluded that Bosentan may not reduce mortality if started late in CLD-related pulmonary hypertension (Drinker 2012). In fact, there is a suggestion that it may be associated with increased mortality in sick newborn infants and thus safety and efficacy needs to be studied further (Moussa 2011).

Overall ETRAs have shown to be beneficial in adults and children with pulmonary arterial hypertension and animal models of PPHN. Hence, there may be a role for them in the management of PPHN. Hence we conducted this systematic review. To our knowledge, there are no systematic reviews on this topic so far.

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Objectives

  1. To assess the efficacy and safety of ETRA in the treatment of PPHN in full-term, post term and late preterm infants.
  2. 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.

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Methods

Criteria for considering studies for this review

Types of studies

We included randomised, cluster-randomised or quasi-randomised controlled trials for this review.

Types of participants

Late preterm (born at 34+0 to 36+6 weeks), term infants (born at 37+0 to 41+6 weeks) and post-term infants ( (ie born after 41+6 weeks of gestation) until postmenstrual age (PMA) up to 44 weeks with PPHN were eligible for inclusion.

The diagnosis of PPHN was either clinical or based on echocardiography. Clinical diagnosis of PPHN was considered when there was hypoxemia refractory to oxygen therapy and mechanical ventilation (Roberts 1997). The echocardiographic diagnosis of PPHN was made by demonstrating the presence of extrapulmonary right to left shunting at the ductal or atrial level, near or supra-systemic pulmonary arterial pressures and doppler evidence of tricuspid regurgitation (Stayer 2010; Dhillon 2012).

Types of interventions

  1. ETRAs - any dose, frequency, duration, timing, mode of delivery.
  2. ETRAs used alone or combined with other pulmonary vasodilator medications.
Comparisons
  1. 'ETRA' versus 'placebo'.
  2. 'ETRA' versus 'no pharmacological pulmonary vasodilators'.
  3. 'ETRA' versus 'other pulmonary vasodilator medications'. The other pulmonary vasodilator medications are inhaled nitric oxide, inhaled or systemic prostaglandins, milrinone or sildenafil.
  4. 'ETRA as an adjunct to iNO' versus 'iNO alone'.
  5. 'ETRA as an adjunct to iNO' versus 'placebo and iNO'.
  6. 'ETRA as an adjunct to 'other pulmonary vasodilators' versus 'other pulmonary vasodilators and placebo'.
  7. 'ETRA as an adjunct to other pulmonary vasodilators' versus 'other pulmonary vasodilators without the use of placebo'.

The dose, route and frequency of other pulmonary vasodilators were as per published neonatal pharmacopoeia guidelines.

Types of outcome measures

Primary outcomes
  1. Death from any cause prior to hospital discharge or need for extracorporeal membrane oxygenation (ECMO)
  2. Requirement for ECMO prior to hospital discharge
  3. Death from any cause prior to hospital discharge
Secondary outcomes
  1. Death from any cause prior to 28 days of life (neonatal period)
  2. Percentage of infants that showed improvement in oxygenation index (OI = FiO2 × MAP × 100/PaO2) by at least 20% within 24 hours of treatment.
  3. Percentage of infants that showed improvement in OI by at least 20% at 48 hours of treatment
  4. Percentage of infants that showed improvement in OI by at least 20% at 72 hours of treatment.
  5. Percentage of infants that showed improvement in OI by at least 20% at the end of treatment.
  6. OI after 30 to 60 minutes of therapy
  7. OI at the end of 24 hours of treatment (Mean and SD)
  8. OI at the end of 48 hours of treatment (Mean and SD)
  9. OI at the end of 72 hours of treatment (Mean and SD)
  10. Duration of iNO therapy (days)
  11. Total duration of mechanical ventilation (days) (Mean and SD)
  12. Length of hospitalisation (days) (Mean and SD)
  13. Cerebral palsy: defined as non-progressive motor impairment characterised by abnormal muscle tone and decreased range or control of movements (diagnosed at or before 24 months of age)
  14. Deafness: defined as bilateral sensorineural hearing loss requiring hearing aids (diagnosed at or before 24 months of age)
  15. Blindness: defined as a corrected visual acuity less than 20/200 (diagnosed at or before 24 months of age)
  16. Adverse neurodevelopmental outcome at 6 months of age
  17. Mild cognitive impairment at 18 to 24 months of age: defined as a Mental Development Index score of greater than 1 standard deviation (SD) below the mean on the Bayley Scales of Infant Development II (BSID II) or a cognitive score greater than 1 SD below the mean on BSID III
  18. Significant cognitive impairment at 18 to 24 months of age: defined as a Mental Development Index (MDI) score of greater than 2 SD below the mean on BSID II or a cognitive score greater than 2 SD below the mean on BSID III
  19. Major neurodevelopmental disability at 18 to 24 months of age defined as one or more of the following: a) BSID III cognitive score or language score greater than 2 SD below the normative mean at 18 to 24 months of age; b) BSID II MDI or Psychomotor Developmental Index (PDI) scores greater than 2 SD below the normative mean; Griffiths GQ scores greater than 2 SD below the mean at 18 to 24 months of age; non-ambulant cerebral palsy (CP); blindness or sensorineural deafness. Any other clinically important outcome reported by authors (not pre-specified)
  20. Systemic hypotension requiring the administration of inotropic agents (after introduction of the trial medication)
  21. Hepatotoxicity (elevated liver enzymes or conjugated hyperbilirubinaemia)
  22. Cardiac arrhythmias

Search methods for identification of studies

We searched MEDLINE (1966 to December 2015) for Clinical Trials (MeSH) OR Controlled Clinical Trials (MeSH) OR Randomised Controlled Trials (MeSH) using the following terms:

Population: Infant-Newborn (MeSH) OR Infant, Newborn, Diseases (MeSH) OR newborn (text word) OR infant (text word) OR neonate (text word) AND Hypertension, pulmonary (MeSH) OR persistent fetal circulation syndrome (MeSH) OR Respiratory failure OR Hypoxemia.

Intervention: (("Receptors, Endothelin/antagonists and inhibitors"[MeSH]) OR "Bosentan" [Supplementary Concept]) OR "Sitaxsentan" [Supplementary Concept]. We also searched using the following text words: Selective Endothelin A(ETA) receptor antagonists (Sitaxentan, Ambrisentan, Atrasentan, BQ-123, Zibotentan), dual endothelin receptor antagonists (Bosentan, Tezosentan, Macitentan), and  Selective ETB receptor antagonists (BQ-788 and A192621).

Comparison: placebo or no pharmacological pulmonary vasodilators.

Outcome: Death, ECMO, cognitive impairment, cerebral palsy, deafness or hearing impairment, blindness or visual impairment, developmental delay, adverse effects.

Electronic searches

We searched the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, December 2015); EMBASE (1980 to December 2015); and CINAHL (1982 to December 2015). We searchd the reference lists of identified trials and electronically published abstracts from the annual meetings of the Pediatric Academic Societies (2000 to 2015). We searched ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (who.int/ictrp/en/ External Web Site Policy) web sites to identify ongoing studies. No language restrictions were applied.

Searching other resources

We searched reference lists of the identified articles and the The Science Citation Index (Web of Science).

Data collection and analysis

We used the standard method of conducting a systematic review as described in the Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0 (Higgins 2011). 

Selection of studies

The study selection was done independently by authors K. More and G. Jape. We excluded studies that were not randomised. Authors K. More and G. Jape independently assessed each study to determine whether it met the pre-defined selection criteria, and resolved any differences by discussion with all members of the review team.

Data extraction and management

Two review authors (K. More, G. Jape) independently extracted the data and entered it into a piloted data extraction form. Co-authors (S. Patole, S. Rao) resolved any differences by group discussion. We contacted authors of the included studies for additional information from their studies or clarification of published data.

Assessment of risk of bias in included studies

The following headings and associated questions (based on the questions in the 'Risk of bias' table) were evaluated by review authors K. More and G. Jape and entered into the 'Risk of bias' table.

  • selection bias
  • performance bias
  • attrition bias
  • reporting bias
  • or any other bias

They resolved differences of opinion by discussion with S. Patole and S. Rao. Authors of the included studies were contacted for clarification regarding the risk of bias in their respective studies. See Appendix 1 for a more detailed description of risk of bias for each domain.

Measures of treatment effect

We expressed treatment effect for dichotomous outcomes as risk ratio, risk difference and number needed to treat to benefit (NNTB), with 95% confidence intervals. We planned to express treatment effect for continuous outcomes as mean difference, with 95% confidence intervals. For harmful effects, we planned to use risk ratio, risk difference and number needed to treat to harm (NNTH), with 95% confidence intervals.

Unit of analysis issues

If available, we planned to combine results from cluster trials with other trials using generic inverse variance methods.

Dealing with missing data

If participant dropout led to missing data then we planned to conduct an intention-to-treat analyses. We endeavoured to obtain missing data from the trial authors.

Assessment of heterogeneity

We assessed statistical heterogeneity using the I² statistic. We graded the degree of heterogeneity as follows: less than 25% — no heterogeneity; 25% to 49% — low heterogeneity; 50% to 74% — moderate heterogeneity; 75% or above — high heterogeneity. If substantial heterogeneity did exist (I² > 50%) between studies for the primary outcomes, we planned to explore reasons for heterogeneity.

Assessment of reporting biases

We planned to assess publication bias using the funnel plot (Egger 1997) if at least 10 studies were included in the meta-analysis.

Data synthesis

For studies with similar type of intervention, we performed a meta-analysis to calculate a weighted treatment effect across trials using the fixed-effect model. For continuous outcomes where data was given as median and range or interquartile range, we planned to convert the values to mean and SD using the formula of Wan 2014.

Quality of evidence

We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, as outlined in the GRADE Handbook (Schünemann 2013), to assess the quality of evidence for the following (clinically relevant) outcomes for the comparison of ETRA versus placebo: death from any cause prior to hospital discharge, percentage of infants that showed improvement in OI by at least 20% by the end of therapy, adverse neurological outcomes at six months of age, cerebral palsy, deafness; and for the comparison of ETRA with iNO versus placebo with iNO: need for ECMO prior to discharge.

Two authors independently assessed the quality of the evidence for each of the outcomes above. We considered evidence from randomized controlled trials as high quality but downgraded the evidence one level for serious (or two levels for very serious) limitations based upon the following: design (risk of bias), consistency across studies, directness of the evidence, precision of estimates and presence of publication bias. We used the GRADEpro Guideline Development Tool to create a ‘Summary of findings’ table to report the quality of the evidence.

The GRADE approach results in an assessment of the quality of a body of evidence in one of four grades:

  1. High: We are very confident that the true effect lies close to that of the estimate of the effect.
  2. Moderate: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
  3. Low: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
  4. Very low: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Subgroup analysis and investigation of heterogeneity

We planned to perform subgroup analyses for:

  • selective and non-selective ETRA. Theoretically, selective blocking of ETA may be preferable because vasoconstriction is mediated via ETA receptors.

Sensitivity analysis

We planned to perform sensitivity analyses to examine the effects of excluding studies with high risk of selection bias (sequence generation and allocation concealment).

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Main results

Description of studies

See below

Results of the search

The literature search identified 2142 titles and abstracts. After removing duplicates and reviewing abstracts, 1980 citations were excluded. Thirty-three full text articles were read, out of which two RCTs — Mohamed 2012 and FUTURE-4 study (Steinhorn 2014) — met the inclusion criteria. (Figure 1). Authors of both studies were contacted for additional data and clarification of published results and methodology, but there was no response.

Included studies

Mohamed 2012 was a single centre, double-blinded, placebo-controlled trial conducted in Saudi Arabia. Eligible participants were term or near term infants (greater than/or equal to 34 weeks) with PPHN. Inhaled NO (iNO), ECMO and other pulmonary vasodilators were not available in their setting. Forty-seven newborn infants (greater than/or equal to 34 weeks' gestation and < 7 postnatal days) were randomised to receive either Bosentan (n = 24) or placebo (n = 23). Bosentan was given orally at a dose of 1 mg/kg/dose twice a day. Efficacy and safety of the intervention were evaluated at three time points (on day 3 of drug therapy, at the end of drug therapy and 2 weeks after discontinuation of drug therapy). Efficacy was defined as resolution of PPHN (OI < 15, normal pulmonary artery pressure < 20 mmHg) and no premature discontinuation of the drug due to drug-related toxicity. Safety was evaluated by monitoring drug-related adverse events. The effect of the intervention on OI values were evaluated at 0, 2, 4, 6, 12, 18, 24, 30 and 36 hours after initiation of intervention, every 8 hours until the end of drug therapy and at the three time points of assessment.

The FUTURE-4 trial was a multicentre, double-blinded, placebo-controlled trial in term or near term infants (> 34 weeks) with PPHN (Steinhorn 2014). Bosentan was the ETRA tested. It was used as an adjunctive therapy to iNO and was given in a dose of 2 mg/kg/dose twice daily orally. iNO and ECMO facilities were available at all centres. Twenty-one neonates (greater than/or equal to 34 weeks' gestation and < 7 postnatal days) with PPHN from 9 centres received the study drug (13 Bosentan, 8 placebo). Both groups had similar gestational age, weight and sex distribution. The Bosentan group had higher baseline OI values and higher rates of parenchymal disease than the placebo group. The primary outcome measures were percentage of participants with treatment failure, time to complete weaning from iNO and time to complete weaning from mechanical ventilation. Treatment failure was defined as the need for ECMO or initiation of alternative pulmonary vasodilator treatment. Secondary outcomes were percentage of participants requiring re-initiation of iNO therapy, percentage of participants with pulmonary hypertension at the end of treatment, change in OI from baseline at 3, 5, 12, 24, 48 and 72 hours following study drug administration, change in arterial blood gas pH, saturation, partial pressure of O₂, partial pressure of CO₂, pre-ductal peripheral O₂ saturation, post-ductal peripheral oxygen saturation, and FiO₂ from baseline to 72 hours following drug administration. The other outcomes were maximum whole blood concentrations (Cmax) and time to maximum whole blood concentration (Tmax) for Bosentan and its metabolites at various points during the study.

The details of the included studies are given in the table of Characteristics of included studies.

Excluded studies

None.

Risk of bias in included studies

Risk of bias assessed for the included studies (Mohamed 2012 and FUTURE-4 (Steinhorn 2014)) are discussed below (Figure 2).

Allocation (selection bias)

Mohamed 2012 was assessed as having low risk of bias on the domain of random sequence generation as computer-generated number sequence was used. It was 'unclear risk' for the FUTURE-4 study.

For the domain of allocation concealment, Mohamed 2012 was assessed as having low risk of bias. Opaque covers were used to cover the drug's container and oro-gastric tubes used to administer the trial medication. This risk was unclear for the FUTURE-4 study.

Blinding (performance bias and detection bias)

Both studies were assessed as having low risk of bias as they used placebo.

Incomplete outcome data (attrition bias)

Mohamed 2012 carried a high risk of attrition bias because 8 out of 23 infants in the placebo group were excluded due to clinical deterioration. The FUTURE-4 study was assessed to have low risk of attrition bias since information on outcomes was available on all study participants (Steinhorn 2014).

Selective reporting (reporting bias)

Mohamed 2012 was considered as having unclear risk of bias since the trial protocol was not available. The FUTURE-4 study was considered as having low risk of bias as all prespecified outcomes were reported (Steinhorn 2014). The trial protocol was available through the ClinicalTrials.gov web site.

Other potential sources of bias

None identified.

Effects of interventions

Endothelin receptor antagonists (ETRA) vs. placebo (comparison 1)

The RCT by Mohamed et al compared 'Bosentan' versus 'placebo' (Mohamed 2012).

Primary outcomes

1. Death from any cause prior to hospital discharge: Mohamed 2012 reported this outcome; there was no significant difference between the Bosentan and placebo group (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 (Analysis 1.1) ( Figure 3). Test for heterogeneity was not applicable.

The outcomes of 'Need for ECMO' and 'Death from any cause prior to hospital discharge or need for ECMO' were not reported by Mohamed 2012 because ECMO facilities were not available in their set up.

Secondary Outcomes

1. Death from any cause prior to 28 days of life (neonatal period): Mohamed 2012 reported this outcome; there was no significant difference between the Bosentan and placebo group (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) (Analysis 1.2). Test for heterogeneity was not applicable.

2. Percentage of infants that showed improvement in OI by at least 20% within 72 hours of treatment: Mohamed 2012 reported on this outcome. There was statistically significant benefit in the Bosentan group (20/24 vs 3/23: RR 6.39, 95% CI 2.19 to 18.63; RD 0.70, 95% CI 0.50 to 0.91; NNTB: 1.4) (Analysis 1.3)(Figure 4). Test for heterogeneity was not applicable.

3. Percentage of infants that showed improvement in OI by at least 20% at the end of treatment: Mohamed 2012 reported on this outcome. There was statistically significant benefit in the Bosentan group (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; NNTB: 1.5). (Analysis 1.4) (Figure 5). Test for heterogeneity was not applicable.

4. Duration of iNO therapy: iNO was not available in the centre where Mohamed 2012 trial was conducted.

5. Total duration of mechanical ventilation (days): In the study by Mohamed 2012, the duration of mechanical ventilation was significantly 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) (Analysis 1.5) (Figure 6). Test for heterogeneity was not applicable.

6. Cerebral palsy: Mohamed 2012 reported on this outcome; there was no significant difference in the incidence of delayed motor development and spasticity at 6 months of age between the Bosentan and placebo group (0/23 vs 3/14; RR 0.09, 95% CI 0.00 to 1.61; RD −0.21, 95% CI −0.44 to 0.01) (Analysis 1.6) (Figure 7). Test for heterogeneity was not applicable.

7. Hearing impairment: Mohamed 2012 reported hearing outcomes at 6 months based on auditory brain stem response (ABR). There was no significant difference in the incidence of hearing impairment between the Bosentan and placebo group (0/23 vs 1/14; RR 0.21, 95% CI 0.01 to 4.79; RD −0.07, 95% CI −0.23 to 0.09) (Analysis 1.7). Test for heterogeneity was not applicable.

8. Adverse neurodevelopmental outcome at 6 months: Mohamed 2012 reported on this outcome. They defined neurologic sequelae as clinical or electrographic proven seizures, abnormal muscle tone, abnormal deep tendon reflexes, delayed motor milestones or abnormal ABR at 6 months. The incidence of such neurologic sequelae was 0/23 in the Bosentan group versus 4/14 in the placebo group (RR 0.07, 95% CI 0.00 to 1.20; RD: −0.29, 95% CI −0.52 to −0.05).(Analysis 1.8). Test for heterogeneity was not applicable.

9. Hepatotoxicity: Mohamed 2012 defined hepatotoxicity as lactate dehydrogenase greater than 1.5 times the upper limit of normal; and alanine aminotransferase or aspartate aminotransferase greater than 3 times the upper limit of normal. None of the infants in the Bosentan or placebo group had evidence of hepatotoxicity.

Mohamed 2012 did not report on the outcomes of OI at the end of 60 minutes, 24 hours, 48 hours and 72 hours of treatment; percentage of infants that showed improvement in oxygenation index by at least 20% within 24 hours and 48 hours of treatment; and length of hospitalisation. Other adverse events such as hypotension or cardiac arrhythmias were also not reported. There was no information on cognitive outcomes or major neurodevelopmental disability at 18 to 24 months.

Other relevant outcomes as reported by the individual studies

Mohamed 2012 defined favourable response if the following three criteria were met: OI less than 15; normal pulmonary artery pressures (< 20 mmHg); and no premature discontinuation of the drug. On day 3 of study therapy, 20/24 (83.3%) were considered to have favourable response compared to 3/23 (13%) in the placebo group. They observed a favourable response in 87.5% of infants treated with Bosentan as compared to 20% in the placebo group (P < 0.0001).

‘Endothelin receptor antagonists (ETRA) + iNO' vs 'placebo + iNO' (comparison 2)

The FUTURE-4 study (Steinhorn 2014) compared 'iNO + Bosentan' versus 'iNO + placebo'

Primary Outcomes:

1. Requirement for ECMO prior to hospital discharge: The FUTURE-4 studyreported on this outcome (Steinhorn 2014). There was no significant difference between the Bosentan and 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) (Analysis 2.1) (Figure 8). Test for heterogeneity was not applicable.

The FUTURE-4 study (Steinhorn 2014) did not report on the outcomes of 'Death from any cause prior to hospital discharge or need for ECMO' and 'Death from any cause prior to hospital discharge'.

Secondary Outcomes:

1. Duration of iNO therapy: The FUTURE-4 trial reported on this outcome (Steinhorn 2014). The median duration of iNO therapy in the Bosentan group was 3.7 days (CI 1.17 to 6.95) versus 2.9 days (CI 1.26 to 4.23) in the placebo group. The difference was not statistically significant (P = 0.34). A forest plot could not be generated since the values were given as median and 95% CI. Test for heterogeneity was not applicable.

2. Total duration of mechanical ventilation (days): In the FUTURE-4 trial the median time to weaning from mechanical ventilation (from first study drug administration) was 10.8 days (CI 3.21 to 12.21) in the Bosentan group versus 8.6 days (CI 3.71 to 9.66) in the placebo group (Steinhorn 2014). The difference was not statistically significant (P = 0.24). Forest plots could not be generated because the results were reported as median and 95% CI. Test of heterogeneity was not applicable.

3. Systemic hypotension requiring the administration of inotropic agents (after introduction of the trial medication): The FUTURE-4 trial reported that Bosentan did not adversely affect systemic blood pressure, but details were not given (Steinhorn 2014). Test for heterogeneity was not applicable.

4. Hepatotoxicity (elevated liver enzymes and or conjugated hyperbilirubinaemia): The FUTURE-4 trial reported that Bosentan did not adversely affect the hepatic transaminase levels (Steinhorn 2014).

The FUTURE-4 study did not report on the outcomes of death from any cause prior to 28 days of life; percentage of infants that showed improvement in oxygenation index by at least 20% within 24 hours, 48 hours, 72 hours and at the end of treatment; OI after 30 to 60 minutes, 24 hours, 48 hours, and 72 hours of therapy; cardiac arrhythmias; total duration of mechanical ventilation; length of hospitalisation; cerebral palsy; deafness; blindness; adverse neurodevelopmental outcome at 6 months of age; cognitive impairment; and major neurodevelopmental disability at 18 to 24 months of age (Steinhorn 2014).

Other relevant outcomes as reported by the individual studies: The FUTURE-4 study reported on OI and change from baseline to 3 hours, 5 hours, 12 hours, 24 hours, 48 hours and 72 hours following the administration of Bosentan (Steinhorn 2014). The values were given as median with 95% confidence intervals. The change from baseline values were as follows:

At 3 hours it was −1.6 (CI −5.1 to 3.3) in the Bosentan group versus 1.1 (CI −6.1 to 6.1) in the placebo group; non-parametric ANCOVA P value = 0.22.

At 5 hours, it was −0.9 (CI −4.7 to 4.5) in the Bosentan versus −5.6 (CI −7.5 to 15.7) in the placebo group; non-parametric ANCOVA P value = 0.15.

At 12 hours, it was −0.8 (CI −12.9 to 2.8) in the Bosentan versus −3.9 (CI −14.6 to 12.5) in the placebo group; non-parametric ANCOVA P value = 0.08.

At 24 hours, it was −4.9 (CI −17.0 to 1.1) in the Bosentan versus −6.9 (CI −9.9 to 19.4) in the placebo group; non-parametric ANCOVA P value = 0.37.

At 48 hours, it was −4.9 (CI −15.5 to −2.1) in the Bosentan versus −9.9 (CI −18.0 to 3.4) in the placebo group; non-parametric ANCOVA P value = 0.06.

At 72 hours, it was −8.9 (CI −23.1 to −1.8) in the Bosentan versus −9.4 (CI −17.7 to 2.2) in the placebo group, non-parametric ANCOVA P value = 0.10.

The FUTURE-4 study also evaluated the pharmacokinetics of Bosentan in the study infants (Steinhorn 2014).

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Discussion

Summary of main results

This systematic review identified two studies that evaluated the efficacy and safety of ETRA in term and late preterm infants with PPHN (Mohamed 2012; Steinhorn 2014). Mohamed 2012 was conducted in a setting where iNO and ECMO were not available, whereas FUTURE-4 trial was a multicentre study where iNO and ECMO were available. Mohamed 2012 used Bosentan as the sole pulmonary vasodilator whereas the FUTURE-4 trial used it as an adjunct therapy to iNO. The sample size in both RCTs was small (Mohamed 2012: 47; Steinhorn 2014: 21).

Mohamed 2012 showed ETRA to be beneficial in improving OI and other short-term respiratory outcomes. There was a trend towards improved neurological outcomes at 6 months in the Bosentan-treated infants. They excluded 8/23 infants in the placebo group from various analyses, which resulted in a high risk of attrition bias. The authors' reasoning for exclusion of those infants was significant clinical deterioration. Hence, it is likely that if those infants were included in the analyses, some of the outcomes might have achieved statistical significance favouring Bosentan. Since the protocol for the study could not be accessed, the study also suffered from unclear risk of reporting bias.

The FUTURE-4 trial found that when used as an adjunct to iNO therapy, Bosentan was safe and well tolerated, but did not improve OI at any time point (3, 5, 12, 24, 48 and 72 hours) (Steinhorn 2014). The study suffered from unequal distribution to the Bosentan group (N = 13) and the placebo group (N = 8) which was likely due to the small number of infants enrolled before the trial was terminated and many sites enrolling the newborns. Since the methods used for generating random sequence numbers and allocation concealment were unclear, the study suffered from unclear risk of selection bias. Since the full publication of the FUTURE-4 trial is awaited, it is difficult to speculate on why Bosentan did not result in improvement in clinically relevant outcomes. One possibility may be the fact that the Bosentan group had higher baseline OI values (21.1 ± 12.95 vs 17.3 ± 11.37) and higher rates of parenchymal lung disease (100% vs 62.5%) than placebo.

The mechanism of action of iNO is via cGMP pathway, whereas the ETRAs act via different a pathway (Steinhorn 2010). Hence, theoretically, it is logical to assume that ETRAs would work synergistically with iNO to improve the outcomes.

A positive upshot from both the studies is that Bosentan was well tolerated and that none of the infants required discontinuation of the study drug because of side effects. While this finding is reassuring, it is important to monitor for safety in future RCTs because a recent meta-analysis in adults found a higher incidence of hepatotoxicity in participants who received Bosentan compared to placebo.

The strength of our study is the fact that it is the first systematic review to evaluate the role of ETRA in PPHN. The weaknesses relate to the small sample size in the included studies.

Overall completeness and applicability of evidence

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

Quality of the evidence

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.

Potential biases in the review process

None to our knowledge.

Agreements and disagreements with other studies or reviews

There are no other published reviews in the neonatal population that have evaluated the role of ETRA in PPHN.

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Authors' conclusions

Implications for practice

The available evidence does not support the use of Bosentan for the treatment of PPHN, either as the sole pulmonary vasodilator or as an adjunct to iNO.

Implications for research

Adequately powered and methodologically robust RCTs are needed to evaluate the efficacy and safety of ETRA in full-term, post-term and late preterm infants with PPHN. In resource-limited settings where iNO is not available, it is ethically and scientifically appropriate to compare ETRA as the sole agent versus placebo. In settings where iNO is available, it will not be ethically appropriate to compare ETRA as the sole agent against placebo because iNO is a well established treatment for PPHN. To overcome that issue, one could consider the following two approaches: (1) compare ETRA to placebo at an early stage in the course of PPHN (ie, at lower oxygen index levels), with strict criteria as to when iNO needs to be commenced, in which one of the primary outcomes of interest would be the 'need for commencement of iNO'; (2) consider ETRA as an adjunct to iNO, similar to the FUTURE-4 Trial (Steinhorn 2014).

Long-term neurodevelopment will also needs to be an important outcome of interest in future RCTs.

It is also important to take into consideration which type of ETRA needs to be tested in RCTs. While theoretically selective ETRAs may be better than non-selective ETRA, adult studies have shown that both non-selective ETRA (eg Bosentan and Tezosentan) and selective ETRA (eg Sitaxsentan and Ambrisentan) improve the outcomes of pulmonary arterial hypertension (Jacobs 2006). Hence future RCTs in newborn infants could have three comparisons: selective ETRA, non-selective ETRA and placebo. Hepatotoxicity and various other potential adverse effects of ETRA need to be carefully monitored in such RCTs.

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Acknowledgements

We wish to thank the editorial staff of the Cochrane Neonatal review committee for their support.

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Contributions of authors

Kiran More conducted independent literature search, selected studies for inclusion, assessed the risk of bias in the included studies, entered the data into Review Manager (RevMan), contacted the authors for additional information, and wrote the first draft of the manuscript.

Gayatri Athayle-Jape conducted independent literature search, selected studies for inclusion, assessed the risk of bias in the included studies, checked the data entered into RevMan by Kiran More, and wrote the final draft of the manuscript.

Shripada Rao directly supervised Kiran More and Gayatri Athayle-Jape throughout various stages of the review, assessed the risk of bias in the included studies, checked the data entered into RevMan by Kiran More, addressed the editors' comments, and edited the final draft of the manuscript.

Sanjay Patole was responsible for the concept and design; and edited the first and the final draft of the review.

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Declarations of interest

Kiran More: none known

Gayatri Athalye-Jape: none known

Shripada Rao: none known

Sanjay Patole: none known

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Differences between protocol and review

  1. The following secondary outcomes of clinical importance have been added
    1. Number of infants that showed improvement in OI by at least 20% at 48 hours of treatment
    2. Number of infants that showed improvement in OI by at least 20% at 72 hours of treatment
    3. OI at the end of 24 hours of treatment (Mean and SD)
    4. OI at the end of 48 hours of treatment (Mean and SD)
    5. OI at the end of 72 hours of treatment (Mean and SD)
    6. Total duration of INO therapy (days; Mean and SD)
    7. Total duration of mechanical ventilation (days; Mean and SD)
    8. Total duration of hospital stay (days; Mean and SD)
    9. Neurodevelopmental outcome at 6 months of age

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Characteristics of studies

Characteristics of included studies

Mohamed 2012

Methods

Study Design: Single Centre, randomised, placebo-controlled, double-blind trial (Saudi Arabia). iNO, ECMO and other pulmonary vasodilators were not available at the study centre.

Study duration: 2 years and 4 months

Study Period: September 2008 to January 2011

Participants

Newborn infants with gestational age greater than/or equal to34 weeks and < 7 postnatal days with PPHN

Mechanical ventilation with FiO₂ > 0.5; and pulmonary hypertension confirmed by echocardiogram

Total number of participants: 47 (24 in Bosentan group and 23 in placebo group)

At the time of entry the mean OI was 43.6 ± 4 in the Bosentan group and 45.1 ± 3 in the placebo group (P > 0.05).

Interventions

Bosentan: 1 mg/kg twice a day, oral; placebo: equal volume of diluent twice a day

Outcomes

Primary Outcomes: a) Efficacy was assessed at three time points (on day 3 of drug therapy, at the end of drug therapy and at 2 weeks after discontinuation of drug therapy). The outcome was considered favourable if all the following criteria were met: OI < 15, normal pulmonary artery pressure (< 20 mmHg), and no premature discontinuation of the drug because of lack of efficacy or drug-related toxicity; b) Safety monitoring for adverse events such as hypotension, gastric intolerance, bleeding or pulmonary haemorrhage. Biochemical parameters such as serum bilirubin, liver enzymes, alkaline phosphatase, serum creatinine, serum electrolytes and complete blood count were performed thrice weekly throughout the drug therapy and at follow-up visits (2 weeks and 6 months after treatment).

Secondary Outcomes: incidence of death (< 28 days), neurologic sequelae, bronchopulmonary dysplasia and reactive airway disease.

Notes  
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Conducted using computer-generated random numbers.

Allocation concealment (selection bias) Unclear risk

Unclear.

Blinding of participants and personnel (performance bias) Low risk

Participants, investigators and nurses were blinded to treatment. Pharmacist maintained the randomisation schedule.

Blinding of outcome assessment (detection bias) Low risk

Investigators were blinded to treatment.

Incomplete outcome data (attrition bias) High risk

8 of 23 participants in the placebo group were excluded from the analysis due to clinical deterioration.

Selective reporting (reporting bias) Unclear risk

The protocol for the study could not be accessed either from a trial registry or from the authors.

Other bias Low risk

None identified.

Steinhorn 2014

Methods

Phase 3, multicentre, randomised, placebo-controlled trial at tertiary centres where iNO was used as a standard of care for PPHN.

Study duration: 2 years (December 2011 to December 2013).

Participants

Newborn infants with gestational age greater than/or equal to 34 weeks and < 7 postnatal days with PPHN, with persistent respiratory failure (OI greater than/or equal to 12) even after at least 4 hours of iNO therapy.

The baseline OI in the Bosentan group was 18.3 (95% CI 8.2 to 35.4) versus 13.2 (95% CI 7.9 to 39.4) in the placebo group.

Interventions

Bosentan (2 mg/kg, twice daily) by nasogastric or orogastric tube versus placebo dispersed in sterile water

iNO was continued in both groups as standard treatment

Outcomes

Primary Outcomes: Percentage of participants with treatment failure; time to complete weaning from iNO; time to complete weaning from mechanical ventilation.

Secondary Outcomes:

  • Percentage of participants requiring re-initiation of iNO therapy
  • Percentage of participants with pulmonary hypertension at the end of treatment
  • Change in OI from baseline to 3, 5, 12, 24, 48, 72 hours following study drug administration
  • Change in arterial blood gas pH, arterial blood oxygen saturation, partial pressure of oxygen in arterial blood, partial pressure of CO₂ in arterial blood, pre-ductal peripheral O₂ saturation, post-ductal peripheral O₂ saturation, fraction of inspired oxygen (FiO₂) from baseline to 72 hours following study drug administration
  • Maximum whole blood concentration (Cmax) for Bosentan and its metabolites Ro 47-8634, Ro 48-5033 and Ro 64-1056 on Day 1 and Day 5
  • Time to Cmax (Tmax) for Bosentan and its metabolites Ro 47-8634, Ro 48-5033 and Ro 64-1056 on Day 1 and Day 5
  • Area under the concentration time curve over a dosing interval at steady state on Day 5 for Bosentan and its metabolites (time frame 5 days)
  • Area under the concentration time curve over a period of 24 hours (dose corrected to 2mg/kg) on day 5 for Bosentan and its metabolites (time frame 24 hours)
  • Accumulation index for Bosentan (time frame 5 days)
Notes  
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Unclear (authors were contacted, but no response)

Allocation concealment (selection bias) Unclear risk

Unclear (authors were contacted, but no response)

Blinding of participants and personnel (performance bias) Low risk

Double-blinded (subject, caregiver, investigator)

Blinding of outcome assessment (detection bias) Low risk

Double-blinded (outcomes assessor)

Incomplete outcome data (attrition bias) Low risk

Follow up outcomes were reported on all study participants

Selective reporting (reporting bias) Low risk

All prespecified outcomes were reported. The protocol for the FUTURE-4 study was available through ClinicalTrials.gov

Other bias Low risk

None identified

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Summary of findings tables

1 Summary of findings

ETRA for PPHN

Patient or population: Neonates with PPHN

Settings: Where facilities for iNO and ECMO were not available

Intervention: ETRA

Comparison: placebo

Outcomes

Illustrative comparative risks

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

ETRA

Death from any cause prior to hospital discharge

3/14

1/23

RR: 0.20 (0.02, 1.77)

One study

37 participants

⊕⊕⊝⊝
Low

Single trial, Small sample size, high attrition bias;

8/23 infants in the placebo group were excluded from analysis

Percentage of infants that showed improvement in OI by at least 20% by the end of therapy

3/15

21/24

4.38 (1.57, 12.17)

One study;

39 participants

⊕⊕⊝⊝
Low

Single trial, Small sample size, high attrition bias;

8/23 infants in the placebo group were excluded from analysis

Adverse neurological outcomes at six months of age

4/14

0/23

0.07 (0.00,1.20)

One study,

37 participants

⊕⊕⊝⊝
Low

Single trial, small sample size, high attrition bias;

8/23 infants in the placebo group were excluded from analysis

Cerebral Palsy

3/14

0/23

0.09 (0.00, 1.61)

One study,

37 participants

⊕⊕⊝⊝
Low

Single trial, small sample size,

8/23 infants in the placebo group were excluded from analysis

Deafness

1/14

0/23

0.21 (0.01, 4.79)

One study,

37 participants

⊕⊕⊝⊝
Low

Single trial, small sample size,

8/23 infants in the placebo group were excluded from analysis

Patient or population: Neonates with PPHN

Settings: Where facilities for iNO and ECMO were available

Intervention: ETRA with iNO

Comparison: placebo with iNO

Need for ECMO prior to discharge

0/8

1/13 (7.7%)

1.93

(0.09, 42.35)

One study,

21 participants

⊕⊕⊝⊝
Low

Small sample size,

Unclear risk

of bias on the domains of random

seq generation

and allocation concealment

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk Ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

2 Summary of findings

ETRA compared with placebo for PPHN

Patient or population: Neonates with PPHN

Settings: Where facilities of iNO and ECMO were not available

Intervention: ETRA

Comparison: placebo

Outcomes

Illustrative comparative risks

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo

ETRA

Total duration of mechanical ventilation

(days)

11.5 ± 0.6

4.3 ± 0.9

MD: −7.20 (−7.64, −6.76)

One study,

37 participants

⊕⊕⊝⊝
Low

only one trial;

Small sample size

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk Ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

3 Summary of findings

ETRA plus iNO compared with placebo plus iNO for PPHN

Patient or population: Neonates with PPHN

Settings: Where facilities for iNO and ECMO were available

Intervention: ETRA plus iNO

Comparison: Placebo plus iNO

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo plus iNO

ETRA plus iNO

Duration of iNO therapy (days)

Median (95% CI)

2.9 (1.26, 4.23)

Median (95% CI)

3.7 (1.17, 6.95)

Not estimable

One study,

21 participants

⊕⊕⊝⊝
Low

Single trial, small sample size,

unclear risk of bias for random sequence generation and

allocation concealment

Total duration of mechanical ventilation

(days)

Median (95% CI) 8.6 days (3.71 to 9.66

Median (95% CI) 10.8 days (3.21 to 12.21)

Not estimable

One study,

21 participants

⊕⊕⊝⊝
Low

Single trial, small sample size,

unclear risk of bias for random sequence generation and

allocation concealment

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk Ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

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References to studies

Included studies

Mohamed 2012

[CRSSTD: 4355799]

Mohamed WA, Ismail M. A randomized, double-blind, placebo-controlled, prospective study of bosentan for the treatment of persistent pulmonary hypertension of the newborn. Journal of Perinatology 2012;32(8):608-13. [CRSREF: 4355800]

Steinhorn 2014

[CRSSTD: 4355801]

NCT01389856: Persistent Pulmonary Hypertension of the Newborn (FUTURE 4). https://clinicaltrials.gov/ct2/show/results/NCT01389856?sect=X01256#all. [CRSREF: 4355802]

* Steinhorn R, Kusic-Pajic A, Cornelisse P, Fineman J, Gehin M, Nowbakht P, et al. Bosentan as adjunctive therapy for persistent pulmonary hypertension of the newborn: Results of the FUTURE-4 study. In: Circulation: American Heart Association's 2014 Scientific Sessions and Resuscitation Science Symposium Chicago, IL United States. 2014. [CRSREF: 4355803]

Excluded studies

None noted.

Studies awaiting classification

None noted.

Ongoing studies

None noted.

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Other references

Additional references

Abman 2007

Abman SH. Recent advances in the pathogenesis and treatment of persistent pulmonary hypertension of the newborn. Neonatology 2007;91(4):283-90.

Abman 2009

Abman SH. Role of endothelin receptor antagonists in the treatment of pulmonary arterial hypertension. Annual Review of Medicine 2009;60:13-23.

Allen 1993

Allen SW, Chatfield BA, Koppenhafer SA, Schaffer MS, Wolfe RR, Abman SH. Circulating immunoreactive endothelin-1 in children with pulmonary hypertension. Association with acute hypoxic pulmonary vasoreactivity. American Review of Respiratory Disease 1993;148(2):519-22.

Ambalavanan 2005

Ambalavanan N, Bulger A, Murphy-Ullrich J, Oparil S, Chen YF. Endothelin-A receptor blockade prevents and partially reverses neonatal hypoxic pulmonary vascular remodeling. Pediatric Research 2005;57(5 Pt 1):631-6.

Barton 2008

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Classification pending references

None noted.

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Data and analyses

1 ENDOTHELIN RECEPTOR ANTAGONISTS (ETRA) vs PLACEBO

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Death from any cause prior to discharge 1 Risk Difference (M-H, Fixed, 95% CI) Subtotals only
  1.1.1 ETRA vs Placebo 1 37 Risk Difference (M-H, Fixed, 95% CI) -0.17 [-0.40, 0.06]
1.2 Death from any cause in the neonatal period (first 28 days of life) 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  1.2.1 ETRA vs Placebo 1 37 Risk Ratio (M-H, Fixed, 95% CI) 0.20 [0.02, 1.77]
1.3 Percentage of infants that showed improvement in OI by at least 20% within 72 hours of treatment 1 47 Risk Ratio (M-H, Fixed, 95% CI) 6.39 [2.19, 18.63]
1.4 Percentage of infants that showed improvement in OI by at least 20% at the end of therapy 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  1.4.1 ETRA vs Placebo 1 39 Risk Ratio (M-H, Fixed, 95% CI) 4.38 [1.57, 12.17]
1.5 Total duration of mechanical ventilation 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
  1.5.1 ETRA vs Placebo 1 47 Mean Difference (IV, Fixed, 95% CI) -7.20 [-7.64, -6.76]
1.6 Cerebral palsy 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  1.6.1 ETRA vs Placebo 1 37 Risk Ratio (M-H, Fixed, 95% CI) 0.09 [0.00, 1.61]
1.7 Deafness 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  1.7.1 ETRA vs Placebo 1 37 Risk Ratio (M-H, Fixed, 95% CI) 0.21 [0.01, 4.79]
1.8 Adverse neurodevelopmental outcome at 6 months 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  1.8.1 ETRA vs Placebo 1 37 Risk Ratio (M-H, Fixed, 95% CI) 0.07 [0.00, 1.20]
 

2 'ENDOTHELIN RECEPTOR ANTAGONISTS (ETRA) plus iNO' vs 'Placebo plus iNO'

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
2.1 Need for ECMO prior to discharge 1 21 Risk Ratio (M-H, Fixed, 95% CI) 1.93 [0.09, 42.35]
 

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Figures

Figure 1

Refer to Figure 1 caption below.

Study flow diagram (Figure 1).

Figure 2

Refer to Figure 2 caption below.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies (Figure 2).

Figure 3 (Analysis 1.1)

Refer to Figure 3 caption below.

Forest plot of comparison: 1 ENDOTHELIN RECEPTOR ANTAGONISTS (ETRA) vs PLACEBO, Outcome: 1.1 Death from any cause prior to discharge (Figure 3).

Figure 4 (Analysis 1.3)

Refer to Figure 4 caption below.

Forest plot of comparison: 1 ENDOTHELIN RECEPTOR ANTAGONISTS (ETRA) vs PLACEBO, Outcome: 1.3 Percentage of infants that showed improvement in OI by at least 20% within 72 hours of treatment (Figure 4).

Figure 5 (Analysis 1.4)

Refer to Figure 5 caption below.

Forest plot of comparison: 1 ENDOTHELIN RECEPTOR ANTAGONISTS (ETRA) for PPHN, outcome: 1.4 Percentage of infants that showed improvement in OI by at least 20% at the end of therapy (Figure 5).

Figure 6 (Analysis 1.5)

Refer to Figure 6 caption below.

Forest plot of comparison: 1 ENDOTHELIN RECEPTOR ANTAGONISTS (ETRA) for PPHN, Outcome: 1.5 Total duration of mechanical ventilation (Figure 6).

Figure 7 (Analysis 1.6)

Refer to Figure 7 caption below.

Forest plot of comparison: 1 ENDOTHELIN RECEPTOR ANTAGONISTS (ETRA) vs PLACEBO, Outcome: 1.6 Cerebral palsy (Figure 7).

Figure 8 (Analysis 2.1)

Refer to Figure 8 caption below.

Forest plot of comparison: 2 'ENDOTHELIN RECEPTOR ANTAGONISTS (ETRA) plus iNO' vs 'Placebo plus iNO', Outcome: 2.1 Need for ECMO prior to discharge (Figure 8).

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Sources of support

Internal sources

  • No sources of support provided

External sources

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA

    Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C.

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Feedback

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Appendices

1 Risk of bias tool

Selection bias (random sequence generation and allocation concealment)
Adequate sequence generation?

For each included study, we categorized the risk of bias regarding sequence generation as:

  • low risk - adequate (any truly random process e.g. random number table; computer random number generator);
  • high risk - inadequate (any non-random process e.g. odd or even date of birth; hospital or clinic record number);
  • unclear risk - no or unclear information provided.
Allocation concealment?

For each included study, we categorized the risk of bias regarding allocation concealment as:

  • low risk - adequate (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
  • high risk - inadequate (open random allocation; unsealed or non-opaque envelopes; alternation; date of birth);
  • unclear risk - no or unclear information provided.
Blinding?
Performance bias

For each included study, we categorized the methods used to blind study personnel from knowledge of which intervention a participant received. (As our study population consisted of neonates, they were all blinded to the study intervention):

  • low risk - adequate for personnel (a placebo that could not be distinguished from the active drug was used in the control group);
  • high risk - inadequate - personnel aware of group assignment;
  • unclear risk - no or unclear information provided.
Detection bias

For each included study, we categorized the methods used to blind outcome assessors from knowledge of which intervention a participant received. (As our study population consisted of neonates they were all blinded to the study intervention). We assessed blinding separately for different outcomes or classes of outcomes. We categorized the methods used with regards to detection bias as:

  • low risk - adequate; follow-up was performed with assessors blinded to group;
  • high risk - inadequate; assessors at follow-up were aware of group assignment;
  • unclear risk - no or unclear information provided.
Incomplete data addressed?
Attrition bias

For each included study and for each outcome, we described the completeness of data including attrition and exclusions from the analysis. We noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported or supplied by the trial authors, we re-included missing data in the analyses. We categorized the methods with respect to the risk attrition bias as:

  • low risk - adequate (< 10% missing data);
  • high risk - inadequate (> 10% missing data);
  • unclear risk - no or unclear information provided.
Free of selective reporting?
Reporting bias

For each included study, we described how we investigated the risk of selective outcome reporting bias and what we found. We assessed the methods as:

  • low risk - adequate (where it is clear that all of the study's pre-specified outcomes and all expected outcomes of interest to the review have been reported);
  • high risk - inadequate (where not all the study's pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study failed to include results of a key outcome that would have been expected to have been reported);
  • unclear risk - no or unclear information provided.
Free of other bias?
Other bias

For each included study, we described any important concerns we had about other possible sources of bias (for example, whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data-dependent process). We assessed whether each study was free of other problems that could put it at risk of bias as:

  • low risk - no concerns of other bias raised;
  • high risk - concerns raised about multiple looks at the data with the results made known to the investigators, difference in number of participants enrolled in abstract and final publications of the paper;
  • unclear - concerns raised about potential sources of bias that could not be verified by contacting the authors.
Overall risk of bias

We made consensus judgements about whether studies were at high risk of bias, according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We assessed the likely magnitude and direction of the bias and whether we considered it as likely to impact on the findings. We planned to explore the impact of the level of bias through undertaking sensitivity analyses - see 'Sensitivity analysis'.


This review is published as a Cochrane review in The Cochrane Library, Issue 8, 2016 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent recent version of the review.