Use of Bosentan in Pediatric Pulmonary Hypertension
Since publication of the Barst study in 2003, more than two dozen papers describing the utility of bosentan in infants and children with PAH have appeared in the medical literature. Because of the relative rarity of this diagnosis, there have been few prospective controlled studies; most of the papers published to date have been observational. In their original paper, Barst and colleagues studied 19 children New York Heart Association (NYHA) functional class II or III who had idiopathic PAH or PAH associated with congenital heart disease. Bosentan produced hemodynamic improvement, with an overall change from baseline mean pulmonary artery pressure of -8.0 mm Hg (95% CI -12.2, -3.7 mm Hg) and in pulmonary vascular resistance index of -300 dyne•s•m/cm (95% CI, -576, -24 dyne•s•m/cm).
Since that initial publication, other investigators have found similar improvement in function with bosentan using larger patient samples, longer treatment duration, or combination therapy. In their 2004 prospective observational study, Ivy and colleagues found that seven of the eight children who were started on bosentan were able to wean their intravenous epoprostenol dose and three were able to have their epoprostenol discontinued. Bosentan was well tolerated by most of the children however one patient discontinued therapy due to elevated liver transaminases. The ability of bosentan to reduce the reliance on injectable medications for PAH is a significant benefit, providing the child and family with a more normal lifestyle.
Maiya and colleagues of the UK Pulmonary Hypertension Service conducted one of the first retrospective pediatric studies of bosentan in 2006. They treated 40 children (ages 1–17 years) with IPAH or PAH associated with other conditions. All but one patient was World Health Organization (WHO) class III or IV. Twenty-five of the children received bosentan as their first treatment. The mean length of therapy was 12.7 months, with a range of 2–24 months. Of the 20 patients with IPAH, 19 demonstrated benefit. In spite of initial stabilization, however, 60% of these patients required epoprostenol. The patients with the least degree of benefit were all under 5 years of age. All 20 of the patients with secondary PAH showed clinical improvement, with improved 6 minute walk tests in the older children, improvement in WHO functional class, and weight gain.
In 2009, investigators from the same program reviewed their experience with 216 children with IPAH or secondary PAH. In the patients with IPAH, monotherapy with bosentan or epoprostenol produced similar rates of survival, with an average of 3.9 years and 3.25 years, respectively. Survival rates were best (4.61 years), however, with combination therapy using bosentan and epoprostenol, with or without sildenafil. For comparison, the National Institutes of Health registry reports a mean survival of only 10 months after diagnosis of PAH in children, significantly shorter than that for adults. An additional paper from this program, published in 2010, provided further support for the use of combination therapy.
In another 2010 paper, Ivy's group evaluated the long-term outcomes of bosentan in 86 children. Early results in these children were published by Rosenzwieg et al. in 2005. The patients (ages 9 months to 18 years) were treated at two centers, Columbia University in New York and the Children's Hospital in Denver. Thirty-six of the children had IPAH and the remaining patients had PAH associated with congenital heart disease or connective tissue disease. Bosentan was initiated as monotherapy or in combination with epoprostenol or treprostinil. Mean treatment duration was 24 months. At last assessment, 24 patients (31%) showed improvement in WHO functional class and 21 (27%) had worsened. Thirteen patients died prior the end of the observation period. All patients required additional therapies. Forty-three (50%) discontinued bosentan due to lack of improvement, PAH deterioration, increased liver transaminases or other adverse effects.
Case Series and Clinical Trials
Since publication of the Barst study in 2003, more than two dozen papers describing the utility of bosentan in infants and children with PAH have appeared in the medical literature. Because of the relative rarity of this diagnosis, there have been few prospective controlled studies; most of the papers published to date have been observational. In their original paper, Barst and colleagues studied 19 children New York Heart Association (NYHA) functional class II or III who had idiopathic PAH or PAH associated with congenital heart disease. Bosentan produced hemodynamic improvement, with an overall change from baseline mean pulmonary artery pressure of -8.0 mm Hg (95% CI -12.2, -3.7 mm Hg) and in pulmonary vascular resistance index of -300 dyne•s•m/cm (95% CI, -576, -24 dyne•s•m/cm).
Since that initial publication, other investigators have found similar improvement in function with bosentan using larger patient samples, longer treatment duration, or combination therapy. In their 2004 prospective observational study, Ivy and colleagues found that seven of the eight children who were started on bosentan were able to wean their intravenous epoprostenol dose and three were able to have their epoprostenol discontinued. Bosentan was well tolerated by most of the children however one patient discontinued therapy due to elevated liver transaminases. The ability of bosentan to reduce the reliance on injectable medications for PAH is a significant benefit, providing the child and family with a more normal lifestyle.
Maiya and colleagues of the UK Pulmonary Hypertension Service conducted one of the first retrospective pediatric studies of bosentan in 2006. They treated 40 children (ages 1–17 years) with IPAH or PAH associated with other conditions. All but one patient was World Health Organization (WHO) class III or IV. Twenty-five of the children received bosentan as their first treatment. The mean length of therapy was 12.7 months, with a range of 2–24 months. Of the 20 patients with IPAH, 19 demonstrated benefit. In spite of initial stabilization, however, 60% of these patients required epoprostenol. The patients with the least degree of benefit were all under 5 years of age. All 20 of the patients with secondary PAH showed clinical improvement, with improved 6 minute walk tests in the older children, improvement in WHO functional class, and weight gain.
In 2009, investigators from the same program reviewed their experience with 216 children with IPAH or secondary PAH. In the patients with IPAH, monotherapy with bosentan or epoprostenol produced similar rates of survival, with an average of 3.9 years and 3.25 years, respectively. Survival rates were best (4.61 years), however, with combination therapy using bosentan and epoprostenol, with or without sildenafil. For comparison, the National Institutes of Health registry reports a mean survival of only 10 months after diagnosis of PAH in children, significantly shorter than that for adults. An additional paper from this program, published in 2010, provided further support for the use of combination therapy.
In another 2010 paper, Ivy's group evaluated the long-term outcomes of bosentan in 86 children. Early results in these children were published by Rosenzwieg et al. in 2005. The patients (ages 9 months to 18 years) were treated at two centers, Columbia University in New York and the Children's Hospital in Denver. Thirty-six of the children had IPAH and the remaining patients had PAH associated with congenital heart disease or connective tissue disease. Bosentan was initiated as monotherapy or in combination with epoprostenol or treprostinil. Mean treatment duration was 24 months. At last assessment, 24 patients (31%) showed improvement in WHO functional class and 21 (27%) had worsened. Thirteen patients died prior the end of the observation period. All patients required additional therapies. Forty-three (50%) discontinued bosentan due to lack of improvement, PAH deterioration, increased liver transaminases or other adverse effects.
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