Bosentan in pediatric patients with pulmonary arterial hypertension

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Article

Reference

Bosentan in pediatric patients with pulmonary arterial hypertension

BEGHETTI, Maurice

Abstract

OBJECTIVE: In order to provide an overview of current knowledge, the literature was systematically examined for clinical studies, which evaluate the safety and effectiveness of bosentan in pediatric pulmonary arterial hypertension (PAH). SOURCES: 3 databases (MEDLINE, EMBASE and BIOSIS) were searched for the period January 2000 - October 2007 using the key words 'pulmonary arterial hypertension', 'bosentan', and 'pediatric patients/children'. RESULTS: Of 165 identified publications, 21 clinical studies were selected:

1 interventional prospective, 6 observational prospective, 5 observational retrospective, and 9 case reports/case series. In the absence of controlled trials, these 21 studies represent the current evidence on the effectiveness and safety of bosentan in the treatment of pediatric PAH. Bosentan appears to improve long-term functional status and hemodynamics in children with PAH but improvement in exercise capacity is not consistently demonstrated. Promising results are reported for the combination of bosentan with other PAH-specific treatments although guidelines for instituting combination therapy have not [...]

BEGHETTI, Maurice. Bosentan in pediatric patients with pulmonary arterial hypertension.

Current Vascular Pharmacology , 2009, vol. 7, no. 2, p. 225-233

PMID : 19356006

Available at:

http://archive-ouverte.unige.ch/unige:19496

Disclaimer: layout of this document may differ from the published version.

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Bosentan in Pediatric Patients with Pulmonary Arterial Hypertension

Maurice Beghetti *

Hôpital des Enfants, Geneva, Switzerland

Abstract: OBJECTIVE: In order to provide an overview of current knowledge, the literature was systematically exam-

ined for clinical studies, which evaluate the safety and effectiveness of bosentan in pediatric pulmonary arterial hyperten- sion (PAH).

SOURCES: 3 databases (MEDLINE, EMBASE and BIOSIS) were searched for the period January 2000 – October 2007 using the key words ‘pulmonary arterial hypertension’, ‘bosentan’, and ‘pediatric patients/children’.

RESULTS: Of 165 identified publications, 21 clinical studies were selected: 1 interventional prospective, 6 observational prospective, 5 observational retrospective, and 9 case reports/case series. In the absence of controlled trials, these 21 stud- ies represent the current evidence on the effectiveness and safety of bosentan in the treatment of pediatric PAH. Bosentan appears to improve long-term functional status and hemodynamics in children with PAH but improvement in exercise ca- pacity is not consistently demonstrated. Promising results are reported for the combination of bosentan with other PAH- specific treatments although guidelines for instituting combination therapy have not been defined. Overall, no safety con- cern is raised by these studies; adverse events, including liver enzyme elevations, appear to be less frequent than reported in the adult PAH clinical trials.

CONCLUSION: Recent experience, although uncontrolled, suggests that bosentan is a well-tolerated and effective ther- apy for pediatric PAH.

Keywords: Bosentan, endothelin, endothelin receptors, pulmonary arterial hypertension, pediatrics.

INTRODUCTION

Pulmonary arterial hypertension (PAH) is a complex dis- ease characterized by vasoconstriction and progressive re- modeling of the pulmonary arterial wall leading to right ven- tricular failure and death. The pathologic features are similar in children and adults but the spectrum of associated condi- tions, clinical presentation, and factors influencing survival differ [1]. The most common etiologies in children after the immediate neonatal period are idiopathic (IPAH), familial, or PAH related to congenital heart disease [1].

Historically, PAH carried a dismal prognosis in children less than 16 years with a median survival of 0.8 years com- pared with 2.8 years in adults [2], mainly as the result of right heart failure. This outcome dramatically improved with the development of chronic vasodilator therapy including calcium channel blockers for acute responders to vasodilator testing and continuous intravenous (i.v.) epoprostenol for non-responders, and some children now survive more than 10 years after diagnosis [3]. Recently, new pharmacologic approaches have demonstrated significant efficacy in the management of adults with PAH; these include prostacyclin analogues delivered subcutaneously (treprostinil [4]) or by inhalation (iloprost [5]), endothelin receptor antagonists

*Address correspondence to this author at the Pediatric Cardiology Unit, Chidren’s University Hospital, Hôpital des Enfants, 6, rue Willy Donzé, 1211 Geneva 14, Switzerland; Tel: +41 22 382458-0; Fax: +41 22 3824546;

E-mail: maurice.beghetti@hcuge.ch

Grant Support: This manuscript was supported by Actelion Pharmaceuticals Ltd.

(bosentan [6, 7], sitaxentan [8], and ambrisentan [9]) and phosphodiesterase type 5 inhibitors (sildenafil [10]).

Bosentan is an antagonist of the ET

_A

/ET

_B

endothelin re- ceptors, which exerts its pharmacologic effects by inhibiting the vasoconstrictor, mitogenic, and remodeling activities of endothelin-1 on the pulmonary arteries [11]. Bosentan im- proves exercise capacity, hemodynamics and time to clinical worsening in adult patients with PAH [6, 7], and also im- proves survival in adult patients with IPAH compared with historical controls [12]. However, no randomized placebo controlled trials have been conducted in pediatric PAH due to the dismal survival in the absence of therapy and the effi- cacy of new therapies in adults. Thus, this systematic review of published data may provide useful information on effec- tiveness and safety of bosentan in children. Bosentan is one of three endothelin receptor antagonists available to clini- cians. However, although the specific ET

A

receptor antago- nists sitaxentan and ambrisentan are used to treat PAH in adults there are no data available on their use in pediatric patients and further pediatric studies are expected in the fu- ture with these substances. To date there appears to be no clear evidence that receptor selectivity is clinically relevant [13].

DATA SOURCE AND STUDY SELECTION

A database search including MEDLINE, EMBASE and

BIOSIS was performed for the period January 2000 – Octo-

ber 2007 using the key words 'pulmonary arterial hyperten-

sion', 'bosentan', and 'pediatric patients/children'. All clinical

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2 Current Vascular Pharmacology, 2009, Vol. 7, No. 2 Maurice Beghetti

studies using bosentan in pediatric PAH were identified and references from the identified articles were reviewed.

Overall 165 publications were identified. Excluded from this list were publications focusing on adult patients, on drugs other than bosentan, or on indications other than PAH.

Hence, 21 clinical studies are included in the present review:

1 interventional prospective [14], 6 observational prospective [1520], 5 observational retrospective [2126], and 9 case reports/case series [27 35] (Table 1). Studies were included irrespective of sample size, geography, study design and quality. Additionally, the search results included 2 comments [36, 37] and 11 reviews [1, 3847] on the pediatric use of bosentan.

CLINICAL STUDIES

One Interventional Prospective Study

I n a two-center, open-label study, Barst et al. [14] de- scribe 19 children (aged 3 to 15 years) with IPAH or PAH related to congenital heart disease (New York Heart Associa- tion functional class (NYHA FC) IIIII). Patients weighing 10 20 kg, 20 40 kg, and over 40 kg received 31.25 mg bosentan once daily, 31.25 mg twice daily (bid), and 62.5 mg bid, respectively, for 1 month, then 31.25 mg bid, 62.5 mg bid and 125 mg bid, respectively, for the remainder of the study. After 12 weeks of treatment, 5 children improved by one NYHA FC and 1 child worsened. Changes in exercise test parameters assessed in children over 8 years of age were variable and not significant. Hemodynamic parameters im- proved; mean pulmonary artery pressure decreased by 8.0 mmHg (95% confidence interval: [12.2; 3.7]) and pulmo- nary vascular resistance index decreased by 300 dyne.s.m

²

/ cm

⁵

(95% confidence interval: [576; 24]). Bosentan showed a similar pharmacokinetic profile as in healthy adults and was well tolerated; the most frequent adverse events were flushing (21%), headache, edema and increased liver aminotransferase activity (16% each). No deaths were re- ported. In the patients concomitantly treated with epopros- tenol, there was no evidence of drug interactions. This study is the current reference for dosing bosentan in children and most studies reviewed hereafter used this regimen, unless otherwise indicated.

Six Observational Prospective Studies

Gilbert et al. [15] report their experience with bosentan in 7 young children (mean age 3.8 years) with congenital heart defects who presented with PAH (NYHA FC IIIII) a) pre- operatively representing a contraindication to corrective sur- gery, or b) persisting after corrective surgery. The children received 1.5 mg/kg/day bosentan for 4 weeks, then the dose was doubled. After a mean follow-up of 8.6 months, bosen- tan had stabilized or improved NYHA FC in all patients (from 2.6 ± 0.6 to 1.7 ± 0.6, p < 0.05) and had significantly reduced right ventricular systolic pressure (from 96 ± 11 to 72 ± 26 mmHg, p < 0.05). One patient showed an increase of liver enzymes to almost 3 times the upper limit of normal (ULN); otherwise, bosentan was well tolerated. Two patients died of cardiac decompensation, 1 due to severe pneumonia and the other following an epileptic seizure.

In another study, Brun et al. [16] followed 14 children (mean age 10 years) with Eisenmenger’s syndrome (NYHA FC IIIII). The patients received a dose of 2 mg/kg/day bosentan for 4 weeks, then the dose was doubled. These authors observed a lasting symptomatic benefit over 12 months: the pulmonary hypertension symptom score in- creased by 2.7 ± 3.3 (p = 0.009). Flat walking and tiredness subscores significantly improved, and a positive trend was seen for climbing stairs. However, there was no improve- ment in mean saturation of oxygen and exercise capacity for the 6 patients able to perform a treadmill test. The authors suggest that these conflicting results could be explained by improved cardiac output following reduced systemic vascu- lar resistance at submaximal exercise, while lower saturation becomes limiting at higher exercise levels. No significant increases in liver enzymes were seen. One patient developed obstructive sleep apnea but the symptoms disappeared after cessation of treatment. No other serious side effects were seen.

Ivy et al. [17] assessed the effect of bosentan in 8 chil- dren (mean age 12.8 years) with IPAH in NYHA FC II III already treated with epoprostenol. After bosentan addition, epoprostenol doses were decreased weekly, depending on stable or decreasing right ventricular peak systolic pressure.

Epoprostenol could be reduced in 7 children without clinical or hemodynamic deterioration, or decrease in aerobic capac- ity; it was even discontinued in 3 patients with stabilization of hemodynamics for up to 1 year. Peak workload and peak oxygen pulse increased (p < 0.05), suggesting an improve- ment in cardiac output. Four patients experienced a liver enzyme elevation and 1 had to discontinue bosentan. This small study indicates that in selected patients, bosentan fa- cilitates the reduction of epoprostenol dose and its associated side effects, without adversely affecting hemodynamic pa- rameters.

Lunze et al. [18] report on 11 patients (median age 12.9 years, 3 adults, 8 children 18 years) with PAH (NYHA FC II III) identified as IPAH or PAH related to congenital heart disease, associated with chronic pulmonary thromboem- bolism or radiotherapy. Patients received combination treat- ment with bosentan (0.75 mg/kg bid for 4 weeks, then 1.5 mg/kg bid) and sildenafil. After a mean follow-up of 1.1 years, clinical benefit was demonstrated by improvements in NYHA FC (from 2.8 ± 0.4 to 1.6 ± 0.8, p = 0.001), in transcutaneous oxygen saturation (from 89.9 ± 9.9 to 92.3 ± 7.1%, p = 0.037), in maximum oxygen uptake (from 18.1 ± 6.8 to 22.8 ± 10.4 mL.min/kg, p = 0.043), and in 6-min walk distance (6MWD) (from 351 ± 58 to 451 ± 119 m, p = 0.039). Mean pulmonary arterial pressure decreased (from 62

± 12 to 46 ± 18 mmHg, p = 0.041). No major side effects regarding liver function and blood pressure regulation were noted but one 6-year old child with IPAH, died of sudden death. Overall, in this patient group including 8 children and 3 adults, a combination of bosentan and sildenafil was well tolerated and effective.

Recently, an observational, disease-based registry was

initiated in Switzerland to collect real-world disease man-

agement experience on pediatric patients with PAH [19]. 23

patients (median age 3 years) with PAH (IPAH (35%), PAH

related to congenital heart disease (52%) or associated with

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Table 1. Clinical Studies on Bosentan in Pediatric PAH.

Study Type Reference Patients

(n)

Age (year)

NYHA Func- tional Class

Additional PAH Treatment

Treatment duration

Interventional prospective

Barst et al. [14] 19 3-15 II-III epoprostenol 12 weeks

Gilbert et al. [15] 7 1.5-6.4 II-III - 8.6 months (mean)

Brun et al. [16] 14 3-18 II-III iloprost 12 months

Ivy et al. [17] 8 6.6-16.2 II-III epoprostenol up to 1 year

Lunze et al. [18] 8 (+3 adults) 5.5-54.7 II-III sildenafil 1.1 years (mean)

Fasnacht et al. [19] 23 0-18 II-IV iloprost

sildenafil

3.5 years (median) Observational

prospective

Beghetti et al. [20] 146 2-11 I-IV sildenafil

prostanoid

29.1 weeks (median)

Maiya et al. [21] 40 0.6-17 III-IV

(1 patient in I)

epoprostenol sildenafil

12.7 months (mean)

Rosenzweig et al. [22] 86 0.7-18 I-IV epoprostenol 14 months (median)

Simpson et al. [24] 7 7 (mean) (2.4) sildenafil

epoprostenol beraprost

35.6 months (median)

Van Loon et al. [25] 10 (+20 adults) - II-IV Sildenafil

treprostinil epoprostenol

2.7 years (median) Observational

retrospective

Penny et al. [26] 7 2.1-14.7 (2.8) epoprostenol 8 months

Hsu et al. [27] 1 1.3 IV - 6 months

Dulac et al. [33] 1 1.3 - 36 months

Rugolotto et al. [28] 1 0.7 - epoprostenol

sildenafil

6 months

Brancaccio et al. [29] 1 7 III epoprostenol

sildenafil

4 years

Beghetti et al. [30] 1 8 - iloprost 3 months

Das et al. [31] 1 (+9 on other treatment)

9 - sildenafil 2 years

Goissen et al. [32] 2 newborns - iNO

epoprostenol sildenafil

-

Nemoto et al. [34] 2 0.4, 0.75 11, 22 days

Single case / Case series

Fraisse et al. [35] 3 4.5, 8 and 14 - - 40, 12, and 6 months

pulmonary diseases (13%)) in NYHA FC IIIV were in- cluded in this registry. One patient died before treatment start and 22 patients were followed for a median of 3.5 years.

At that time, 19 patients were receiving bosentan (9 as monotherapy and 10 in combination with iloprost and/or sildenafil; 3 patients were treated with other medications).

Over a 2-year period, NYHA FC remained stable (19 pa- tients) or improved from III to II (3 patients). An initial im- provement in 6MWD was observed in 6 of 13 evaluated pa-

tients, which was sustained in 4 patients. As most patients were receiving bosentan, these data suggest that the disease is stabilized in bosentan-treated pediatric patients.

Beghetti et al. [20] have published data from a prospec-

tive internet-based post-marketing surveillance system fo-

cused on collecting real-world safety experience with bosen-

tan. Registry results in the pediatric population (2–11 years)

were compared with those in the population 12 years. Over

30 months, 4,994 patients were entered into the surveillance

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program, including 146 bosentan-naïve children aged 2–11 years. The majority of children were in NYHA FC II (28.1%) or III (50.7%) and predominant etiologies were IPAH (40.4%) and PAH related to congenital heart disease (45.2%). The median exposure to bosentan was 29.1 weeks in children 2–11 years and 29.7 weeks in patients 12 years.

Cases of elevated liver aminotransferases and discontinua- tions were fewer in children 2–11 years (2.7% vs. 7.8% and 14.4% vs. 28.1%, respectively). These data provide ‘real world’ evidence on the safety profile of bosentan in young children with PAH.

Five Observational Retrospective Studies

Maiya et al. [21] report on their institution’s experience with bosentan in 40 children, 20 with IPAH (mean age 8.0 years) and 20 with PAH associated with other conditions (mean age 8.3 years). Thirty-nine patients were in NYHA FC IIIIV, 1 was in FC I. Bosentan was given as first line ther- apy in 25 children, whereas 9 children were already treated with epoprostenol and 6 with sildenafil. Mean follow-up was 12.7 months. In the IPAH group, 19 children stabilized with bosentan: no significant changes were observed in NYHA FC, 6MWD, and weight gain, although 12 patients required combined treatment with epoprostenol. In contrast, in pa- tients with PAH associated with other conditions, significant improvements were reported for NYHA FC (p = 0.001), 6MWD (+128 m, p = 0.002), and weight gain (+17.5%, p = 0.01). At study end, 39 patients (97%) were still treated with bosentan and 1 patient (3%) had died. All 15 patients ini- tially treated with epoprostenol or sildenafil improved with the addition of bosentan. In 1 patient, aspartate aminotrans- ferase activity increased to less than 2 times the ULN. The adverse effects often reported in adults receiving bosentan, including headache, dizziness, cough, dyspnea, and flushing [7], were not observed. None of the 4 patients with Eisen- menger’s syndrome experienced a significant fall in systemic arterial oxygen saturation. The authors conclude that bosen- tan stabilizes children with IPAH whereas it improves the clinical status of children with PAH associated with other diseases.

From a retrospective study across 2 centers, Rosenzweig et al. [22] report on the long-term effects of bosentan with or without concomitant prostanoid therapy in a cohort of 86 children (mean age at bosentan initiation 11 years) with IPAH, PAH related to congenital heart disease, or PAH as- sociated with connective tissue disease (NYHA FC I-IV).

Out of 78 patients with NYHA FC assessments at bosentan initiation and at one follow-up, 36 (46%) improved by at least one NYHA FC (p < 0.001) and 8 patients (10%) wors- ened by 1 class. The median follow-up of these patients was 12 months. In 49 children who had hemodynamic assess- ments within a 3 month period preceding bosentan initiation, modest but significant hemodynamic improvements were demonstrated at cardiac catheterization with a median fol- low-up of 9 months. Mean pulmonary artery pressure and pulmonary vascular resistance decreased (64 ± 3 to 57 ± 3 mmHg, p = 0.005, and 20 ± 2 to 15 ± 2 U·m

²

, p = 0.01, respectively). At the end of the observation period, 68 patients (79%) still received bosentan, 13 (15%) had discon- tinued, and 5 (6%) had died (median exposure to bosentan 14 months). At 2 years, the survival was 91% (88% for IPAH

and 96% for secondary PAH). Asymptomatic increases in liver aminotransferases were reported in 10 patients (12%), leading to discontinuation in 3. The most frequent adverse events were peripheral edema (8%) and systemic hypoten- sion (3%). Two patients (2%) with unrepaired congenital heart disease discontinued bosentan due to systemic arterial oxygen desaturation. Three patients died in the subgroup starting bosentan with concomitant prostanoid therapy: two from hemoptysis and acute respiratory distress syndrome, and 1 from worsening right heart failure. Two patients died from right heart failure in the subgroup starting bosentan without prostanoid therapy. All deaths were considered to be due to the clinical progression of PAH. This study was sub- sequently extended to a median follow-up of 30 months [23], at which time 25 (29%) patients were continuing bosentan.

Five (6%) patients discontinued bosentan due to liver func- tion test abnormalities. Disease had progressed in 53% at 3 years (n = 20 patients at risk). Survival in patients on bosen- tan at 1, 2, 3 and 4 years was 98% (n = 69 patients at risk), 88% (n = 42), 82% (n = 27) and 82% (n = 16), respectively.

Simpson et al. [24] report on 7 children (mean age 7.4 years) with IPAH treated with bosentan as first line therapy (adding, when necessary, first sildenafil, then epoprostenol).

Survival and clinical status in these patients were compared with a group of 12 historical control patients (mean age 6.9 years) who were diagnosed prior to the availability of epo- prostenol, bosentan, and sildenafil, and who received only conventional therapy including anticoagulants and calcium channel blockers. The median bosentan treatment duration was 13.6 months (5.2 to 21 months) for monotherapy and 35.6 months (7.7 to 40.7 months) for combination with sild- enafil. Freedom from initiation of epoprostenol was 100% at 12 months, 83% at 34 months and 41.7% at 45 months.

There were no adverse effects attributed to bosentan or sild- enafil, including no increase in hepatic transaminase activity.

One patient died of a pulmonary hypertensive crisis 37 months after presentation, during an anesthetic insertion of a central venous catheter for intravenous epoprostenol. Sur- vival in the bosentan-treated group was 100% at 36 months and 75% at 60 months, compared with 33% at both time- points in the historic control group (p = 0.044 by log-rank test). The authors conclude that treatment with bosentan de- lays IPAH disease progression and, in combination with other therapies, improves survival.

Van Loon et al. [25] describe the effectiveness of bosen- tan in 30 patients (20 adults, 10 children) with PAH related to congenital heart disease (NYHA FC II-IV) for a median follow-up period of 2.7 years. In the whole group, initial (4 months) improvements in NYHA FC and 6MWD were maintained throughout the first year but were followed by a decline at 2.7 years. The decline in walk distance occurred earlier in children (after 1 year). The persistence of the bene- ficial effect of bosentan at 1 and 2 years was 78% and 57%

in adults, and 50% and 20% in children, respectively. Three

deaths occurred during the study at 0.5 month (hemoptysis

associated with acute circulatory failure), 8.4 months (pro-

gressive right ventricular failure) and 37.2 months (infection

of the epoprostenol delivery system). In this study, the worse

outcome observed in children could have been caused by a

more severe disease at baseline.

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In an abstract, Penny et al. [26] report their experience with bosentan in 7 children with IPAH (median age 9.5 years) treated for 8 months. In the majority of children, bosentan was associated with an improvement in sympto- matic status (mean NYHA FC decreased from 2.8 to 2.1) and a decrease in pulmonary vascular resistance index (3 out of 4 evaluated patients had a decrease from 18.4 U·m

²

to 10.1 U.m

²

). There was no adverse effect and no deterioration of liver function.

Nine Case Reports/Case Series

The treatment of pediatric PAH with bosentan as mono- or combined therapy is further documented in 9 single case reports/case series [27 35].

In 2 separate studies, Hsu et al. [27] and Dulac et al. [33]

reported on the use of bosentan in two 16 month-old children with IPAH. In both cases, the patient’s parents refused epo- prostenol treatment and bosentan was administered at a dos- age of 15.6 mg twice daily (Hsu et al. [27] initiated bosentan at a dosage of 15.6 mg once daily in the first month). After 6 months of treatment, improvements were reported for the functional status and quality of life [27, 33], as well as in stabilization of echocardiographic parameters that was main- tained after 36 months of therapy [33]. Regular biological exams showed good hepatic and hematological tolerance.

Rugolotto et al. [28] describe the use of bosentan (10 mg bid, doubled 1 month later) and concomitant epoprostenol, followed by the addition of sildenafil, in an 8 month-old in- fant suffering from severe bronchopulmonary dysplasia and PAH. Four months after treatment initiation, systolic right ventricular pressure measured by echocardiography had de- creased from 68% to 40% of the systemic level. The combi- nation therapy was well tolerated. Epoprostenol and subse- quently bosentan were discontinued while sildenafil treat- ment was pursued at a lower dose. The patient subsequently died from septic shock and refractory hypoxia.

Brancaccio et al. [29] and Beghetti et al. [30] report the cases of a 7 year-old and an 8 year-old child, respectively, with severe IPAH treated with combination therapy of epo- prostenol, bosentan, and sildenafil [29] or iloprost and bosentan [30]. In the first case [29], functional status im- proved from class III to class II, which allowed a gradual weaning and discontinuation from prostacyclin. After 4 years of combined treatment, the child had satisfactorily grown in height and weight; the latest echocardiogram showed right atrial and ventricular enlargement with half systemic pres- sure in the right ventricle; the 6MWD was 430 m and the patient was in NYHA FC I. The combination of bosentan and sildenafil was well tolerated. In the second case [30], after 3 months of combined treatment, the 6MWD had in- creased from 295 m to 400 m. There was a significant reduc- tion in right ventricular size and normalization in interven- tricular septal curvature. The patient’s quality of life im- proved and lung transplantation could be postponed. This case shows that combined bosentan and iloprost therapy can be associated with remarkable improvements in children with PAH.

Das et al. [31] describe 10 children that underwent car- diac catheterization after recovery from high altitude pulmo-

nary edema, and were found to have chronic pulmonary hy- pertension. In one 9 year-old boy who developed persistent pulmonary hypertension despite calcium channel blockers and moving to a lower altitude, oral bosentan and sildenafil were added to the treatment regimen. After 2 years, the pa- tient had improved exercise tolerance with an estimated sys- tolic pulmonary arterial pressure of 50 mmHg.

Use of bosentan in newborns is reported for the first time by Goissen et al. [32]. These authors describe 2 cases of per- sistent pulmonary hypertension of the newborn (PPHN) complicating a transposition of the great arteries with intact ventricular septum (TGA/IVS). Both infants had failed to respond to usual management (correction of hypotension, inhaled nitric oxide, epoprostenol infusion) and to oral silde- nafil, and they could not have repair surgery. In both cases, PPHN resolved within 3 days after starting bosentan (1 mg/kg bid). The arterial switch surgical procedure could subsequently be performed. No adverse effect was associated with the use of bosentan. This favorable response to treat- ment suggests a possible role for bosentan in the treatment of newborn infants with PPHN complicating TGA/IVS.

Nemoto et al. [34] report their experience with bosentan in 2 children (aged 5 and 9 months) with sustained pulmo- nary hypertension in the acute phase after surgical correction of a complete atrioventricular septal defect and closure of a ventricular septal defect. As symptoms did not improve fol- lowing the administration of sildenafil, bosentan (1.5 mg/kg/day) was added. Symptoms of sustained pulmonary hypertension alleviated in both patients and sildenafil was gradually reduced and stopped. When signs of pulmonary hypertension had resolved, bosentan therapy was also stopped after 11 and 22 days. Bosentan caused a transient increase in liver aminotransferase in the 5-month-old child that resolved upon discontinuation.

In a case series, Fraisse et al. [35] describe 3 children (aged 4.5, 8 and 14 years) with end-stage PAH and recurrent syncope treated by atrial septostomy along with combined epoprostenol and bosentan (31.25, 62.5, and 125 mg bid).

Within a few weeks, the NYHA FC improved from III to II in all 3 patients. No syncope occurred and the children re- mained in NYHA FC II during follow-up (6 40 months).

This small case series demonstrates that children with end- stage PAH may benefit from atrial septostomy associated with combined epoprostenol - bosentan therapy.

DISCUSSION

In the last decade, therapeutic advances have considera- bly improved the outcome of patients with various forms of PAH. Despite increasing knowledge regarding treatment of PAH in adult patients, there are limited data describing the response to treatment and survival in children. In general, children with PAH are treated with the clinical strategies used in adults. In current treatment algorithms for adults [48]

and children [49], bosentan treatment is considered for NYHA FC III patients with a negative response to acute vasoreactivity testing and for patients who do not have a sustained response to calcium channel blockers (Fig. (1)).

Bosentan therapy may also be an oral alternative to prosta-

noid infusion in severe PAH, especially for patients refusing

invasive therapy. In children, the efficacy and safety of

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bosentan is supported by a number of prospective and retro- spective studies of varied size and design but no controlled trials. Most of these studies are observational and do not follow the methodologic rules associated with randomized controlled trials but they do have inherent strengths [50]:

taken together, they provide typical routine care data from a large number of children with PAH (n = 388) who are treated with bosentan therapy for 1 day up to over 12 years.

Thus, they provide a fairly extensive 'real world' experience on the effectiveness and safety of bosentan. Although bosen- tan is only commercially available in tablets of 62.5 mg and 125 mg, which can be difficult to administer to children, a pediatric formulation, in the form of a dispersible tablet with an adjustable dosing of 8 to 32 mg, is currently undergoing clinical evaluation in children in Europe and in the USA.

Effectiveness

Functional and hemodynamic improvements have been demonstrated in placebo-controlled clinical trials of bosentan in adult patients with PAH [6, 7] but no controlled trials have been performed in children.

In real-world clinical settings, for children with PAH, the change in NYHA FC is often used to measure disease pro- gression. As reported for adults [6, 7], most children treated with bosentan (including the youngest under 6 years of age) improve or stabilize their NYHA FC for treatment durations of up to 2 years [14, 15, 22, 26 and unpublished results].

This benefit is also reported in single cases or case series [27, 29, 35] The improvements may be more pronounced in PAH related to another condition than in IPAH [21].

The 6MWD is a useful tool to detect changes in exercise tolerance and endurance. However, in clinical trials and clini- cal practice, exercise capacity measurements are limited by concerns of feasibility and reliability, especially in the very young [14, 51, 52]. In pediatric patients with PAH related to congenital heart disease, van Loon et al. [25] observe an improvement in 6MWD after 4 months but a decline after 1 year. Brun et al. [16] also report a decrease in exercise ca- pacity after 1 year of treatment in children with Eisenmen- ger’s syndrome who could perform a treadmill test. Maiya et al. [21] find that the improvement at 1 year in 6MWD is significant in patients with PAH related to a secondary con- dition but not in those with IPAH. Thus, in children, the

Fig. (1). Pediatric pulmonary arterial hypertension treatment guidelines (a ’Responder’ is defined as a patient who has a significant response to acute pulmonary vasodilator testing with a reduction in mean pulmonary artery pressure of at least 20%, with no change or an increase in cardiac output (reproduced with permission from reference [49]).

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long-term benefit of bosentan could not be established via the measurement of exercise capacity, perhaps confounded by methodological issues.

Pulmonary hemodynamic measurements are widely used in randomized controlled trials in adults to evaluate the re- sponse to treatment [53] even though they are not always strongly correlated to functional status and exercise capacity [54]. In several pediatric observational studies [14, 15, 22, 26], serial cardiac catheterization or echocardiography was performed and suggested modest but significant hemody- namic improvements after up to 9 months of bosentan treat- ment.

In 2 separate pediatric studies [21, 22, 55], 97% and 79%

patients continued bosentan treatment after a median follow- up of 12.7 and 14 months, respectively, and 29% continued after 30 months [55]. Survival has only been assessed in 1 retrospective study [22] and its longer-term extension [55];

Rosenzweig et al. report high survival rates after 2 years especially for patients with PAH related to congenital heart disease (96%) compared with IPAH (88%). After 4 years, the survival was still 82% [55]. Although most children sta- bilize or improve with bosentan treatment, some quickly deteriorate [21, 22, 55]. The occurrence of sudden death is not unexpected in this population, since children with PAH are prone to develop syncope resulting in sudden death [18, 21, 24, 56]. However, most deaths are associated with clini- cal worsening due to PAH progression [22, 24] presenting as a decrease in exercise capacity or the development of right ventricular failure [15].

Safety Profile

The pediatric studies did not reveal any unexpected safety signals beside the known safety profile of bosentan established in the clinical trials in adults [7, 12]. The primary elimination of bosentan is via hepatic metabolism, which could result in hepatocellular injury in some patients, espe- cially in children with an immature hepatic metabolism.

However, no safety concern was apparent in children treated according to the dosing recommendation of Barst et al. [14], i.e., for children weighing 1020 kg, 2040 kg, and over 40 kg, 31.25 mg once daily, 31.25 mg bid, and 62.5 mg bid for 1 month, then 31.25 bid, 62.5 bid and 125 mg bid, respec- tively. In most studies, liver function tests remained within normal limits [16, 18, 24, 26, 27, 33]. When hepatic function abnormalities were present, they were transient or resolved following dose reduction [15, 17, 21] or discontinuation (3%

of all patients [22 and unpublished results]). These results are in line with the findings from the bosentan post- marketing surveillance program, which shows a lower rate of elevated liver enzymes in children 2 11 years than in pa- tients 12 years [20, 57].

Other adverse effects previously noted in adult patients receiving bosentan, including headache, dizziness, cough, dyspnea, and flushing [7, 12], are not consistently reported in children [14, 15, 21, 22]. In the largest pediatric study to date, Rosenzweig et al. [22] report peripheral edema (8%), systemic hypotension (3%), and systemic arterial oxygen desaturation leading to discontinuation in patients with unre- paired congenital heart disease (2%). On the other hand, in a study including 4 patients with Eisenmenger’s syndrome,

none experienced a significant fall in systemic arterial oxy- gen saturation [21].

Combination Therapy

The combination of drugs with different mechanisms of action and different metabolic pathways is an attractive therapeutic option to address the multiple pathophysiologic mechanisms present in PAH [58] while reducing dosing and side effects. Although only uncontrolled and limited suppor- tive data are available, combination therapy is frequently used in clinical practice [14]. Epoprostenol and sildenafil use was not allowed in the 2 phase III trials of bosentan [6, 7]

but in some of the pediatric studies reported here, many pa- tients were already receiving epoprostenol or sildenafil, prior to bosentan initiation [14, 21, 22, 32 and unpublished re- sults]. Two studies report further improvements in functional status and /or hemodynamics following the addition of bosentan [14, 21]. However, in a third study [22], the im- provement was less pronounced possibly because the pa- tients receiving epoprostenol at baseline tended to have more severe disease.

The latest international recommendations [59] suggest that combination therapy is an option for adult patients not responding sufficiently to endothelin receptor antagonists or non-parenteral prostanoids. This approach may provide a substantial treatment advantage for children with PAH by delaying the initiation of intravenous epoprostenol. Two small studies document the benefits of adding sildenafil to bosentan: NYHA FC, hemodynamics, exercise capacity [18]

and survival [24] improved and the need to commence intra- venous epoprostenol was delayed [24]. These studies are limited by their retrospective design without control, a small number of patients, and the comparison of data from differ- ent treatment eras. The combination of bosentan and iloprost also led to a dramatic improvement in exercise capacity and echocardiography parameters in a case of severe IPAH [30].

Although these results are promising, long-term prospective studies are required to establish the impact of bosentan com- bined with other agents on functional status and survival in childhood PAH.

Until recently, continuous i.v. epoprostenol was the only treatment for severe unreactive pulmonary hypertension. It is a very challenging therapy for the family and the child, with painful side effects and serious complications [60]. There- fore, in a number of studies, the epoprostenol dose was de- creased after adding less invasive PAH treatments in an at- tempt to decrease epoprostenol-related side effects. This ap- proach is supported by the work of Ivy et al. [17] who report that, in selected patients, bosentan facilitates the reduction of epoprostenol dosage without adversely affecting hemody- namic parameters. In line with these results, Brancaccio et al. [29] used a combination of bosentan and sildenafil to wean a 7-year-old girl with severe PAH from epoprostenol.

The above studies do not reveal any safety concern re-

lated to the use of bosentan in combination with epopros-

tenol or sildenafil. Combination therapy is generally well

tolerated [14, 18, 2124, 29 and unpublished results]. Phar-

macokinetic interaction between bosentan and epoprostenol

is unlikely since the drugs have different metabolic and ex-

cretory pathways and the pharmacokinetics of bosentan are

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not affected by concomitant treatment with epoprostenol [14, 61, 62]. On the other hand, sildenafil inhibits CYP3A4 activ- ity and thus leads to an increase in bosentan plasma concen- trations [63]. It is unknown whether this increases the poten- tial of bosentan to cause liver damage but, in the bosentan post-marketing surveillance of about 5000 patients, the com- bination of bosentan and sildenafil (n = 119) was not associ- ated with an increased rate of aminotransferase elevations [57]. Conversely, bosentan reduces the plasma concentration of sildenafil in patients with PAH [63] and increasing the sildenafil dose might be justified in patients treated with chronic bosentan.

Clearly more data are needed to provide efficacy and safety evidence for future combination treatment strategies.

Although current guidelines suggest that combination ther- apy is a possible option for patients with NYHA FC III PAH who respond poorly to monotherapy, the criteria for institut- ing combination therapy have not been defined.

CONCLUSIONS

In children, evidence for the effectiveness and safety of bosentan is supported by a number of prospective and retro- spective studies of varied sample size and design. This sug- gests that the results obtained in adult patients may be ex- trapolated to children, thus offering a well-tolerated and ef- fective therapy that is easy to administer. However, addi- tional long-term prospective studies may be required to es- tablish the impact of bosentan alone, and in combination with other agents, on survival and functional status in pediat- ric PAH.

ACKNOWLEDGEMENTS

The author thanks Sylvie I. Ertel, PhD, who provided medical writing services on behalf of Actelion Pharmaceuti- cals Ltd.

CONFLICT OF INTEREST

Maurice Beghetti is a consultant, advisory board mem- ber, and investigator for Actelion, advisory board member for Mondo Biotech, Pfizer, Encysive, GlaxoSmithKline, EliLilly and Bayer Schering, he has received consultant grant from INO Therapeutics.

ABBREVIATION

6MWD = 6-Minute walk distance bid = Twice daily CCB = Calcium channel blockade

ERA = Endothelin receptor antagonist FC = Functional class

iNO = Inhaled nitric oxide

IPAH = Idiopathic pulmonary arterial hypertension i.v. = Intravenous

NYHA = New York Heart Association

PAH = Pulmonary arterial hypertension PDE-5 = Phospodiesterase type 5

PGI

2

= Prostacyclin

PPHN = Persistent pulmonary hypertension of the newborn

TGA/IVS = Transposition of the great arteries with intact ventricular septum

ULN = Upper limit of normal

REFERENCES

[1] Widlitz A, Barst RJ. Pulmonary arterial hypertension in children.

Eur Respir J 2003; 21(1): 155-76.

[2] D'Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991; 115(5): 343-9.

[3] Yung D, Widlitz AC, Rosenzweig EB, Kerstein D, Maislin G, Barst RJ. Outcomes in children with idiopathic pulmonary arterial hypertension. Circulation 2004; 110(6): 660-5.

[4] Simonneau G, Barst RJ, Galie N, Naeije R, Rich S, Bourge RC, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary hypertension. Am J Respir Crit Care Med 2002; 165: 1-5.

[5] Goldsmith DR, Wagstaff AJ. Inhaled iloprost: in primary pulmonary hypertension. Drugs 2004; 64(7): 763-73; discussion 774-5.

[6] Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tap- son VF, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001; 358(9288): 1119-23.

[7] Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346(12): 896-903.

[8] Barst RJ, Langleben D, Badesch D, Frost A, Lawrence EC, Shapiro S, et al. Treatment of pulmonary arterial hypertension with the se- lective endothelin-A receptor antagonist sitaxsentan. J Am Coll Cardiol 2006; 47(10): 2049-56.

[9] Galie N, Badesch D, Oudiz R, Simonneau G, McGoon MD, Keogh AM, et al. Ambrisentan therapy for pulmonary arterial hyperten- sion. J Am Coll Cardiol 2005; 46(3): 529-35.

[10] Michelakis ED, Tymchak W, Noga M, Webster L, Wu XC, Lien D, et al. Long-term treatment with oral sildenafil is safe and improves functional capacity and hemodynamics in patients with pulmonary arterial hypertension. Circulation 2003; 108(17): 2066-9.

[11] Clozel M. Effects of bosentan on cellular processes involved in pulmonary arterial hypertension: do they explain the long-term benefit? Ann Med 2003; 35(8): 605-13.

[12] McLaughlin VV, Sitbon O, Badesch DB, Barst RJ, Black C, Galie N, et al. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J 2005; 25(2): 244-9.

[13] Opitz CF, Ewert R, Kirch W, Pittrow D. Inhibition of endothelin receptors in the treatment of pulmonary arterial hypertension: does selectivity matter? Eur Heart J 2008; 29(16): 1936-48.

[14] Barst RJ, Ivy D, Dingemanse J, Widlitz A, Schmitt K, Doran A, et al. Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension. Clin Pharmacol Ther 2003; 73: 372-82.

[15] Gilbert N, Luther YC, Miera O, Nagdyman N, Ewert P, Berger F, et al. Initial experience with bosentan (Tracleer) as treatment for pulmonary arterial hypertension (PAH) due to congenital heart disease in infants and young children. Z Kardiol 2005; 94: 570-4.

[16] Brun H, Thaulow E, Fredriksen PM, Holmstrom H. Treatment of patients with Eisenmenger's syndrome with Bosentan. Cardiol Young 2007; 17: 288-94.

[17] Ivy DD, Doran A, Claussen L, Bingaman D, Yetman A. Weaning and discontinuation of epoprostenol in children with idiopathic pulmonary arterial hypertension receiving concomitant bosentan.

Am J Cardiol 2004; 93: 943-6.

[18] Lunze K, Gilbert N, Mebus S, Miera O, Fehske W, Uhlemann F, et al. First experience with an oral combination therapy using bosen- tan and sildenafil for pulmonary arterial hypertension. Eur J Clin Invest 2006; 36 Suppl 3: 32-8.

(10)

[19] Fasnacht MS, Tolsa JF, Beghetti M. The Swiss registry for pulmonary arterial hypertension: The paediatric experience. Swiss Med Wkly 2007; 137: 510-3.

[20] Beghetti M, Hoeper M, Kiely DG, Carlsen J, Schwierin B, Hum- bert M. Safety experience with bosentan in 146 children 2–11 years with pulmonary arterial hypertension: results from the European post-marketing surveillance programme. Pediatr Res 2008; 64:

200-4.

[21] Maiya S, Hislop AA, Flynn Y, Haworth SG. Response to bosentan in children with pulmonary hypertension. Heart 2006; 92: 664-70.

[22] Rosenzweig EB, Ivy DD, Widlitz A, Doran A, Claussen LR, Yung D, et al. Effects of long-term bosentan in children with pulmonary arterial hypertension. J Am Coll Cardiol 2005; 46: 697-704.

[23] Ivy DD, Barst RJ, Doran AK, Lemarie J-C, Brand M, Rosenberg D, et al. Effects of Long-Term Bosentan in Children with Pulmo- nary Arterial Hypertension. Cardiology in the Young 2008;

18(Suppl 1): 1–106. Abstract PW3-6.

[24] Simpson CM, Penny DJ, Cochrane AD, Davis AM, Rose ML, Wilson SE, et al. Preliminary experience with bosentan as initial therapy in childhood idiopathic pulmonary arterial hypertension. J Heart Lung Transplant 2006; 25: 469-73.

[25] van Loon RL, Hoendermis ES, Duffels MG, Vonk-Noordegraaf A, Mulder BJ, Hillege HL, et al. Long-term effect of bosentan in adults vs. children with pulmonary arterial hypertension associated with systemic-to-pulmonary shunt: does the beneficial effect per- sist? Am Heart J 2007; 154: 776-82.

[26] Penny DJ, Rose M, Wilson S, Davis AM, Weintraub RG. Prelimi- nary experience with bosentan in children with primary pulmonary hypertension. J Am Coll Cardiol 2003: 485A.

[27] Hsu H-H, Wu E-T, Chen J-S, Wu M-H, Wang J-K, Ko W-J, et al.

Bosentan is an alternative treatment option in a child with severe idiopathic pulmonary artery hypertension and abnormal liver enzymes. Respiratory Med Extra 2005; 1: 140-143.

[28] Rugolotto S, Errico G, Beghini R, Ilic S, Richelli C, Padovani EM.

Weaning of epoprostenol in a small infant receiving concomitant bosentan for severe pulmonary arterial hypertension secondary to bronchopulmonary dysplasia. Minerva Pediatr 2006; 58: 491-4.

[29] Brancaccio G, Toscano A, Bevilacqua M, Di Chiara L, Parisi F.

Bosentan and sildenafil: should the combination therapy be a valid alternative in childhood to prostacyclin infusion? Pediatr Tran- splant 2007; 11: 110-2.

[30] Beghetti M, Nicod L, Barazzone-Argiroffo C, Rimensberger PC.

New combined treatments avoided transplantation in a child with severe pulmonary hypertension. Heart 2004; 90: 154.

[31] Das BB, Wolfe RR, Chan KC, Larsen GL, Reeves JT, Ivy D. High- altitude pulmonary edema in children with underlying cardiopul- monary disorders and pulmonary hypertension living at altitude.

Arch Pediatr Adolesc Med 2004; 158: 1170-6.

[32] Goissen C, Ghyselen L, Tourneux P, Krim G, Storme L, Bou P, et al. Persistent pulmonary hypertension of the newborn with transpo- sition of the great arteries: successful treatment with bosentan. Eur J Pediatr 2008; 167: 437-40.

[33] Dulac Y, Bassil R, Gressin V, Bonnet S, Acar P. Bosentan therapy for pulmonary arterial hypertension: a case 16-month-old boy. Curr Med Res Opin 2007; 23: S103-S107.

[34] Nemoto S, Yoshimura S, Matsumura M, Nishimura K. An initial experience of endotherine-1 dual-receptor blockade in the treatment of sustained pulmonary hypertension early after congenital cardiac surgery in infancy. Kyobu Geka 2007; 60: 453-6.

[35] Fraisse A, Paoli F, Gressin V, Amin Z, Simmoneau G, Humbert M.

Atrial septal fenestration in children for treatment of end-stage pulmonary hypertension. Curr Med Res Opin 2007; 23: s97-s101.

[36] Adatia I. Improving the outcome of childhood pulmonary arterial hypertension: the effect of bosentan in the setting of a dedicated pulmonary hypertension clinic. J Am Coll Cardiol 2005; 46: 705-6.

[37] Standing JF. Long-term bosentan treatment in children with pulmonary arterial hypertension. J Am Coll Cardiol 2006; 47: 1914-5;

author reply 1915.

[38] Beghetti M. Current treatment options in children with pulmonary arterial hypertension and experiences with oral bosentan. Eur J Clin Invest 2006; 36 Suppl 3: 16-24.

[39] Rosenzweig EB, Widlitz AC, Barst RJ. Pulmonary arterial hypertension in children. Pediatr Pulmonol 2004; 38: 2-22.

[40] Tulloh R. Management and therapeutic options in pediatric pulmonary hypertension. Expert Rev Cardiovasc Ther 2006; 4: 361-74.

[41] Abman SH. Pulmonary hypertension in older children: new approaches and therapies. Paediatr Respir Rev 2006; 7 Suppl 1: S177- 9.

[42] Donti A, Formigari R, Ragni L, Manes A, Galie N, Picchio FM.

Pulmonary arterial hypertension in the pediatric age. J Cardiovasc Med (Hagerstown) 2007; 8: 72-7.

[43] Rashid A, Ivy D. Pulmonary hypertension in children. Curr Paed 2006; 16: 237-247.

[44] Fraisse A, Habib G. [Treatment of pulmonary arterial hypertension in children]. Arch Pediatr 2004; 11: 945-50.

[45] Schulze-Neick I. [PAH in congenital heart defects--therapeutic experiences with children and adults]. Kinderkrankenschwester 2005; 24: 259-60.

[46] Rosenzweig EB, Barst RJ. Pulmonary arterial hypertension: A comprehensive review of pharmacological treatment. Treat Respir Med 2006; 5: 117-127.

[47] Ricachinevsky CP, Amantea SL. Treatment of pulmonary arterial hypertension. J Pediatr (Rio J) 2006; 82(5 Suppl): S153-65.

[48] Galie N, Branzi A. Pulmonary arterial hypertension: therapeutic algorithm. Ital Heart J 2005; 6: 856-60.

[49] Rosenzweig EB, Barst RJ. Idiopathic pulmonary arterial hypertension in children. Curr Opin Pediatr 2005; 17: 372-80.

[50] Avorn J. In defense of pharmacoepidemiology--embracing the yin and yang of drug research. N Engl J Med 2007; 357: 2219-21.

[51] Garofano RP, Barst RJ. Exercise testing in children with primary pulmonary hypertension. Pediatr Cardiol 1999; 20: 61-4; discussion 65.

[52] Gorenflo M, Nelle M, Schnabe PA, Ullmann MV. Pulmonary hypertension in infancy and childhood. Cardiol Young 2003; 13:

219-27.

[53] Channick RN, Simonneau G, Robbins IM, Frost A, Tapson VF, Badesch DB, et al. Bosentan, a dual endothelin receptor antagonist, improves exercise capacity and hemodynamics in patients with pulmonary arterial hypertension: Results of a double blind, randomized placebo-controlled trial. Circulation 2000; 102 (Abst 476).

[54] Hoeper MM, Oudiz RJ, Peacock A, Tapson VF, Haworth SG, Frost AE, et al. End points and clinical trial designs in pulmonary arterial hypertension: clinical and regulatory perspectives. J Am Coll Car- diol 2004; 43(12 Suppl S): 48S-55S.

[55] Ivy D, Barst R, Doran A, Lemarie J-C, Brand M, Rosenberg D, et al. Effects of Long-Term Bosentan in Children with Pulmonary Ar- terial Hypertension. Accepted as poster presentation at the 43rd Annual Meeting of the Association for European Paediatric. Cardi- ology May 21 - 24, 2008.

[56] Krishnan U. Diagnosis and management of primary pulmonary hypertension. Indian J Pediatr 2000; 67: 523-7.

[57] Humbert M, Segal ES, Kiely DG, Carlsen J, Schwierin B, Hoeper MM. Results of European post-marketing surveillance of bosentan in pulmonary hypertension. Eur Respir J 2007; 30: 338-44.

[58] Galie N, Seeger W, Naeije R, Simonneau G, Rubin LJ. Compara- tive analysis of clinical trials and evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol 2004;

43(12 Suppl S): 81S-88S.

[59] Badesch DB, Abman SH, Simonneau G, Rubin LJ, McLaughlin VV. Medical therapy for pulmonary arterial hypertension: updated ACCP evidence-based clinical practice guidelines. Chest 2007;

131: 1917-28.

[60] Galie N, Manes A, Branzi A. Medical therapy of pulmonary hypertension. The prostacyclins. Clin Chest Med 2001; 22: 529-37.

[61] Weber C, Gasser R, Hopfgartner G. Absorption, excretion, and metabolism of the endothelin receptor antagonist bosentan in healthy male subjects. Drug Metab Dispos 1999; 27: 810-5.

[62] Brash AR, Jackson EK, Saggese CA, Lawson JA, Oates JA, Fitz- Gerald GA. Metabolic disposition of prostacyclin in humans. J Pharmacol Exp Ther 1983; 226: 78-87.

[63] Paul GA, Gibbs JS, Boobis AR, Abbas A, Wilkins MR. Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension. Br J Clin Pharmacol 2005; 60: 107-12.

Received: ?????????? Revised: ??????????????? Accepted: ??????????????