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Efficacy and Safety of Bosentan for Pulmonary Arterial Hypertension in Adults With Congenital Heart Disease
Efficacy and Safety of Bosentan for Pulmonary Arterial Hypertension in Adults With Congenital Heart Disease Oliver Monfredi, MBChB, MRCPa, Linda Griffiths, RGN, RSCNb, Bernard Clarke, MDa,b, and Vaikom S. Mahadevan, MDa,b,* The dual endothelin receptor antagonist, bosentan, has been shown to be well tolerated and effective in improving pulmonary arterial hypertension (PAH) symptoms in patients with Eisenmenger syndrome but data from longer-term studies are lacking. The aim of this study was to retrospectively analyze the long-term efficacy and safety of bosentan in adults with PAH secondary to congenital heart disease (PAH-CHD). Prospectively collected data from adult patients with PAH-CHD (with and without Down syndrome) initiated on bosentan from October 2007 through June 2010 were analyzed. Parameters measured before bosentan initiation (62.5 mg 2 times/day for 4 weeks titrated to 125 mg 2 times/day) and at each follow-up (1 month and 3, 6, 9, 12, 18, and 24 months) included exercise capacity (6-minute walk distance [6MWD]), pretest oxygen saturation, liver enzymes, and hemoglobin. Data were analyzed from 39 patients with PAH-CHD (10 with Down syndrome) who had received >1 dose of bosentan (mean duration of therapy 2.1 ⴞ 1.5 years). A significant (p <0.0001) average improvement in 6MWD of 54 m over a 2-year period in patients with PAH-CHD without Down syndrome was observed. Men patients had a 6MWD of 33 m greater than women (p <0.01). In all patients, oxygen saturation, liver enzymes, and hemoglobin levels remained stable. There were no discontinuations from bosentan owing to adverse events. In conclusion, patients with PAH-CHD without Down syndrome gain long-term symptomatic benefits in exercise capacity after bosentan treatment. Men seem to benefit more on bosentan treatment. Bosentan appears to be well tolerated in patients with PAH-CHD with or without Down syndrome. © 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;108:1483–1488) Bosentan has been widely studied and used to treat patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD). It is a dual endothelin receptor antagonist that blocks endothelin A and endothelin B receptors. In the Bosentan Randomized Trial of Endothelin Antagonist Therapy–5 (BREATHE-5) study bosentan was shown to improve exercise capacity and pulmonary hemodynamics in patients with Eisenmenger syndrome.1 Based on these data, bosentan is the only endothelin receptor antagonist currently recommended for treatment of Eisenmenger syndrome.2,3 Questions remain, however, over the sustained efficacy of bosentan in the mid to long term. Some studies have demonstrated sustained beneficial effects,4,5 whereas others have shown that beneficial effects of the drug decrease with longer-term use.6,7 We conducted a retrospective analysis of our database of all adults with PAH-CHD including Eisenmenger
a
Cardiovascular Research Group, School of Biomedicine, University of Manchester, Manchester, United Kingdom; bManchester Heart Centre, Manchester Royal Infirmary, Manchester, United Kingdom. Manuscript received June 9, 2011; revised manuscript received and accepted July 5, 2011. Grant support for statistical analysis of the data and writing assistance during the development of the article was provided by Actelion Pharmaceuticals, London, United Kingdom. *Corresponding author: Tel: ⫹44-161-276-8098; fax: ⫹44-161-2765138. E-mail address: [email protected] (V.S. Mahadevan). 0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2011.07.006
physiology treated with bosentan at our institution—a tertiary adult congenital cardiac center—to assess efficacy, safety, and tolerability in the medium to long term. Methods Data on all adult patients (ⱖ18 years old, with and without Down syndrome) with PAH-CHD who were referred to and received PAH therapy at our tertiary adult congenital cardiac center were prospectively collected in a dedicated database. Data recorded include patient demographics, underlying cardiac diagnoses, baseline medications, and hemodynamic, efficacy, and safety parameters. Before treatment initiation, all patients who give consent undergo right and left heart catheterization and hemodynamic parameters such as mean pulmonary arterial pressure and ratio of pulmonary to systemic pressure are measured. Where possible, exercise capacity (using the 6-minute walk distance [6MWD] test) and oxygen saturation levels at rest (using pulse oximetry or by blood sampling) are measured before bosentan initiation and subsequently at each follow-up visit. Owing to inherent difficulties in accurately assessing exercise capacity in patients with Down syndrome, 6MWD is analyzed only for patients without Down syndrome. Laboratory measurements of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and hemoglobin levels are measured before bosentan initiation and at each follow-up visit. Adverse events are recorded throughout treatment. www.ajconline.org
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Table 1 Patients’ demographics and underlying congenital heart defect Variable
Patients Without Down Syndrome (n ⫽ 29)
Patients With Down Syndrome (n ⫽ 10)
All Patients (n ⫽ 39)
40.72 ⫾ 14.25 36 (22–67) 18 (62%) 11 (38%)
32.70 ⫾ 8.06 33 (22–49) 5 (50%) 5 (50%)
38.67 ⫾ 13.32 34 (22–67) 23 (59%) 16 (41%)
Age at treatment initiation (years) Mean ⫾ SD Median (range) Women Men Race White/British Asian Other ethnic group Does not wish to state Congenital heart defect Ventricular septal defect Atrioventricular septal defect Transposition of great arteries with ventricular septal defect Secundum atrial septal defect Pulmonary atresia with or without septal defect Aortopulmonary window Patent ductus arteriosus Truncus arteriosus Tricuspid atresia
20 (69%) 5 (17%) 3 (10%) 1 (3%)
9 (90%) — — 1 (10%)
29 (74%) 5 (13%) 3 (8%) 2 (5%)
9 (31%) 2 (7%) 5* (17%) 3 (10%) 4 (14%) 2 (7%) 2 (7%) 1 (3%) 1 (3%)
3 (30%) 7 (70%) — — — — — — —
12 (31%) 9 (23%) 5* (13%) 3 (8%) 4 (10%) 2 (5%) 2 (5%) 1 (3%) 1 (3%)
* Includes 1 patient with congenitally corrected transposition of the great arteries.
All patients initiated on bosentan from October 2007 through June 2010 were included in this retrospective analysis. Data collected up to December 2010 were analyzed. Bosentan was initiated at 62.5 mg 2 times/day for the first 4 weeks and was titrated up to 125 mg 2 times/ day thereafter in all patients except 1 owing to tolerability issues. Data were analyzed using SAS 9.2 (SAS Institute, Cary, North Carolina). Patients were included in the analysis only if they had a baseline (before bosentan initiation) and ⱖ1 postbaseline (after bosentan initiation) parameter. Categorical data are described by frequency and percentage; continuous data are summarized by their mean ⫾ SD or median and range. Pretest oxygen saturation, 6MWD, AST, ALT, and hemoglobin were analyzed at all visits from baseline until treatment month 24 (i.e., baseline, months 1, 3, 6, 9, 12, 18, and 24.). Absolute and mean change from baseline values in 6MWD with no imputation for missing values and last observation carried forward (LOCF) imputation to account for missing values were analyzed. Predictors of change from baseline in 6MWD response to treatment were examined using repeated-measures multivariate linear random effects regression model, with baseline oxygen saturation, age, gender, ethnicity, and diagnosis as covariates. The same random effects models (with random intercept, slope, and quadratic terms), which does not impute for missing values or make LOCF assumptions, were also used to test for changes from baseline over time, with significance set at the p ⬍0.05 level for all parameters. Absolute pretest oxygen saturation was summarized separately for patients with and without Down syndrome with and without LOCF imputation. Changes from baseline in oxygen saturation were analyzed by a repeated-measures linear effects regression model with random intercept. The relation between change from baseline in 6MWD and oxygen saturation level was
Table 2 Baseline cardiovascular, anticoagulant, and iron-replacement medications Medications
Amiodarone Digoxin Bisoprolol Candesartan Enalapril Irbesartan Ramipril Sotalol Diltiazem Amiloride Bumetanide Co-amilofruse Eplerenone Furosemide/frusemide Spironolactone Aspirin* Clopidogrel Warfarin Atorvastatin Simvastatin Ferrous sulfate Sodium feredetate Vitamin B12 injections
Patients Without Patients With Down Syndrome Down Syndrome (n ⫽ 27) (n ⫽ 9) 1 (4%) 4 (15%) 6 (22%) 1 (4%) 2 (7%) — 2 (7%) 1 (4%) 1 (4%) — 1 (4%) 1 (4%) 2 (7%) 8 (30%) 3 (11%) 10 (37%) 1 (4%) 15 (56%) 1 (4%) 2 (7%) 4 (15%) — 1 (5%)
— — — — — 1 (11%) — 1 (11%) — 1 (11%) 1 (11%) — — 3 (33%) 1 (11%) 3 (33%) — 3 (33%) — 1 (1%) 2 (22%) 1 (11%) —
All Patients (n ⫽ 36) 1 (3%) 4 (11%) 6 (17%) 1 (3%) 2 (6%) 1 (3%) 2 (6%) 2 (6%) 1 (3%) 1 (3%) 2 (6%) 1 (3%) 2 (6%) 11 (31%) 4 (11%) 13 (36%) 1 (3%) 18 (50%) 1 (3%) 3 (8%) 6 (17%) 1 (3%) 1 (3%)
* Two patients received warfarin or clopidogrel concomitantly with aspirin.
examined for patients without Down syndrome using a graphical approach and quantified using Spearman correlation coefficient. For AST, ALT, and hemoglobin levels, data were summarized for all patients with and without LOCF imputation.
Congenital Heart Disease/Treatment Outcomes in PAH-CHD Patients
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Figure 1. Six-minute walk distance for patients without Down syndrome treated for up to 24 months with bosentan. (A) Absolute values for all patients. (B) Absolute values (mean ⫾ SD) for all patients with no imputation for missing values. (C) Absolute values (mean ⫾ SD) for all patients with last observation carried forward imputation to account for missing values. (D) Change from baseline values (mean ⫾ SD) for all patients with last observation carried forward imputation to account for missing values. CI ⫽ confidence interval.
Results The database included 39 patients with PAH-CHD, 10 of whom had Down syndrome, all having received ⱖ1 dose of bosentan. Three patients (1 with Down syndrome) were already on bosentan when referred to our center. Bosentan was initiated in all patients who were naive to other PAHspecific drugs, with the exception of 1 patient without Down syndrome who was already taking sildenafil 50 mg 3 times/ day. In all but 2 patients bosentan was maintained as monotherapy; 1 patient was also given sildenafil 16 months after starting bosentan and another was given sildenafil 2 years 2 months after starting bosentan, which was subsequently discontinued owing to poor tolerability. One patient stopped taking bosentan for 4 months after 18 months of treatment because she wanted to start a family; however, subsequent symptomatic worsening prompted a decision to restart the drug. Patient demographics are presented in Table 1. Most patients were on anticoagulant/antiplatelet therapies, principally warfarin or aspirin, and use of other cardiac drugs including  blockers, angiotensin-converting enzyme inhibitors, calcium channel blockers, and diuretic medications
was common (Table 2). Of the 8 patients on iron-replacement therapy, 6 were women. Eisenmenger syndrome was present in 35 patients (90%). Underlying congenital cardiac defects and demographics are listed in Table 1. Four patients had undergone surgical repair or palliations for the defect or its consequences (surgical repair of an atrioventricular septal defect, Mustard procedure in a patient with transposition of the great arteries with ventricular septal defect, Waterston shunt for tricuspid atresia, and stenting for pulmonary arterial stenosis in a patient with previous repair of a ventricular septal defect). Mean pulmonary arterial pressure in those who underwent cardiac catheterization before bosentan initiation was 72.3 ⫾ 18.6 mm Hg (n ⫽ 19), with a mean ratio of pulmonary to systemic pressure of 0.95 ⫾ 0.17 (range 0.48 to 1.33, n ⫽ 24). With the exception of 1 patient with Down syndrome, all patients were successfully titrated to bosentan 125 mg 2 times/day daily after 4 weeks of taking bosentan 62.5 mg 2 times/day. The patient who was initially unable to tolerate the increase in dose was successfully uptitrated to bosentan
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Figure 2. Mean oxygen saturation levels at rest before a 6-minute walk test for patients without and with Down syndrome treated for up to 24 months with bosentan. Absolute values (mean ⫾ SD) for (A) patients without Down syndrome with no imputation for missing values, (B) patients without Down syndrome with last observation carried forward imputation to account for missing values, (C) patients with Down syndrome with no imputation for missing values, and (D) patients with Down syndrome patients with last observation carried forward imputation to account for missing values. Abbreviation as in Figure 1.
125 mg 2 times/day 2 years 8 months after initiation of therapy. Mean durations of bosentan treatment from date of commencement to latest/final 6MWD test or liver function test were 2.1 ⫾ 1.5 years (median 1.7) for all patients (n ⫽ 39), 2.2 ⫾ 1.3 years (median 1.8) for patients without Down syndrome (n ⫽ 29), and 2.0 ⫾ 2.2 years (median 1.3) for patients with Down syndrome (n ⫽ 10). Individual data from patients without Down syndrome (n ⫽ 25, 4 patients excluded from analyses because baseline data were not available) showed that 6MWD improved from baseline at almost every time point (Figure 1), with mean improvements from baseline value (293 ⫾ 108 m) achieved at each time point for absolute values, absolute values for LOCF, and change from baseline values for LOCF. The postbaseline average increase in 6MWD of 54 m was highly statistically significant (p ⬍0.0001 vs no increase, random effects model). Male gender was a predictor of 6MWD response to bosentan, with men having a statistically significantly higher average increase in 6MWD of 33 m compared to women (p ⫽ 0.016, random effects model). There were no other statistically significant predictors of response among the other covariates tested including age, ethnicity,
diagnosis, and baseline oxygen saturation at rest. For patients without Down syndrome, mean pretest oxygen saturation was 84.6 ⫾ 6.0% at baseline (n ⫽ 25) and remained stable throughout treatment with bosentan (Figure 2), with no statistically significant change over time (p ⫽ 0.24, random effects linear regression model with random intercept). There was no statistically significant relation between change in 6MWD and change in oxygen saturation in this patient group (p ⫽ 0.8). Oxygen saturation levels for patients with Down syndrome also remained stable throughout bosentan treatment (Figure 2). Before bosentan treatment mean levels of AST were 27.9 ⫾ 9.5 IU (n ⫽ 34, 3 patients without Down syndrome and 2 with Down syndrome were excluded from analysis because baseline data were not available) and those of ALT were 21.9 ⫾ 8.4 IU (n ⫽ 36, 2 patients without Down syndrome and 1 with Down syndrome were excluded from analysis because baseline data were not available). There was no clinically relevant or statistically significant increase in either liver enzyme during bosentan treatment. For patients with data at month-24 levels were 24.9 ⫾ 4.5 IU (n ⫽ 13) for AST and 17.3 ⫾ 5.2 IU (n ⫽ 14) for ALT.
Congenital Heart Disease/Treatment Outcomes in PAH-CHD Patients
Month-24 LOCF values were 28.7 ⫾ 10.3 IU (n ⫽ 34) for AST and 20.7 ⫾ 8.2 IU (n ⫽ 36) for ALT. For the 2 analyses month-24 levels for these liver enzymes were within the normal range (0 to 40 for AST and 0 to 45 for ALT). Mean pretreatment baseline hemoglobin levels were 18.2 ⫾ 4.1 g/dl (n ⫽ 36, 2 patients without Down syndrome and 1 with Down syndrome were excluded from analysis because baseline data were not available) and 18.2 ⫾ 2.6 g/dl for patients with data at month 24 (n ⫽ 14) and 18.3 ⫾ 2.8 g/dl (n ⫽ 36) for month-24 LOCF. No significant changes in hemoglobin levels were observed with bosentan treatment. Twenty-two adverse events were reported in 16 patients (41%), namely headache (n ⫽ 10), lower-limb edema (n ⫽ 4), nasopharyngitis (n ⫽ 3), heavy legs (n ⫽ 2), flushing, interaction with warfarin, and itchy skin (n ⫽ 1). No patient discontinued the drug because of adverse events. Seven patients died during the follow-up period. Causes of death were stroke (n ⫽ 1), respiratory complications (n ⫽ 1), and progressive heart failure (n ⫽ 1) in the 3 patients with Down syndrome. Causes of mortality in patients without Down syndrome included sudden cardiac death (presumed arrhythmia, n ⫽ 2), cerebral abscess (n ⫽ 1), and hemoptysis (n ⫽ 1). None of these deaths were considered related to bosentan treatment in the opinion of the treating clinician. Discussion These data provide evidence that patients without Down syndrome with PAH-CHD gain long-term symptomatic benefit in exercise capacity without detrimental effects on systemic oxygen saturation after treatment with bosentan. In addition, it provides supportive evidence that bosentan is well tolerated in patients with PAH-CHD with and without Down syndrome. Retrospective analyses of small numbers of patients without Down syndrome with PAH-CHD (n ⫽ 6 to 17) previously naive to advanced PAH therapy have shown improvements in 6MWD from 34 to 142 m after 6 months of bosentan therapy8,9 and from 27 to 66 m after 15 months of therapy.10,11 Prospective open-label studies with small numbers of treatment-naive patients without Down syndrome and with PAH-CHD of around 1 year in duration have similarly found improvements in 6MWD from 34 to 74 m.4,12–14 We report a significant (p ⬎0.0001) average improvement in 6MWD of 54 m over a 2-year observation period in patients without Down syndrome with PAH-CHD. To our knowledge there are only 2 other contemporary reports, which were retrospective database analyses, of improvements in exercise capacity for up to 2 years with endothelin receptor antagonist monotherapy in patients with PAHCHD. Eighteen adult patients without Down syndrome followed up for a mean period of 29 months had a significant improvement of 124 m after 2 years of bosentan monotherapy.5 Another study of 53 patients, which included adults with and without Down syndrome (mean bosentan or sitaxsentan treatment duration of 15 months), showed a mean 88-m improvement at 2 years for all patients and a 108-m improvement in the Down syndrome patient subgroup.15
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In our study male gender was a predictor of a better response to bosentan therapy, with men having a greater increase in 6MWD than women. To the best of our knowledge, this is the first time such an observation has been reported. The reason for this is unknown. When we retrospectively examined baseline 6MWD there were no differences between men and women (295 ⫾ 126 vs 291 ⫾ 100 m, p ⫽ 0.9, Wilcoxon test). There was a significant difference in hemoglobin levels between men and women without Down syndrome at baseline (20.9 ⫾ 3.2 vs 16.3 ⫾ 3.9 g/dl, respectively, p ⫽ 0.011, Wilcoxon test), although not at the last available observation (19.9 ⫾ 2.6 vs 17.2 ⫾ 2.7 g/dl, respectively, p ⫽ 0.074, Wilcoxon test). All patients underwent baseline and 6-month checks on ferritin/ iron levels and 5 patients without Down syndrome required iron-replacement therapy. Of these patients who received iron-replacement therapy 4 were women. It has recently been shown that iron replenishment can improve exercise tolerance in patients with Eisenmenger syndrome.16 Based on this, it is clear the observed effect of a greater increase in 6MWD in men in our study is not attributable to iron therapy. However, iron reserves may be lower in women of menstruating age. In concordance with other studies of advanced therapy in PAH-CHD1,7,9,11,12,14,15 there was no change in levels of systemic oxygen saturation at rest in patients with and without Down syndrome in this study. Bosentan was well tolerated by all patients in this study. Adverse events were reported by ⬍1/2 of all patients and were typical of those observed in randomized controlled trials of bosentan.1,17,18 None of the 7 deaths were attributed to the drug but were considered owing to recognized comorbidities of CHD. No patient had increased liver enzymes in this study necessitating withdrawal of the drug, consistent with other studies in patients with PAH-CHD.4,11 Hemoglobin levels remained stable for all patients in this study. Within the recognized limitations of this being an uncontrolled retrospective analysis of data collected in a realworld clinical situation, our study substantially adds to growing evidence that advanced PAH therapies have a longterm beneficial role in the treatment of patients with PAHCHD, in particular in those with Eisenmenger syndrome. One of the principal limitations in our study is incomplete data owing to patients missing clinic visits, inability to perform the 6MWD test, or not being on therapy long enough to contribute data to each time point analyzed. However, LOCF analysis for each parameter did support the data derived from the analyses where data were missing. The BREATHE-5 randomized placebo-controlled study provided evidence of short-term improvements in hemodynamics and exercise capacity after treatment with bosentan in patients with Eisenmenger syndrome1 and its open-label extension showed these improvements lasted up to 40 weeks of treatment.14 Our study shows symptomatic benefit can be gained for periods ⬎2 years. It has recently been shown that advanced PAH therapies confer a survival advantage to patients with Eisenmenger syndrome compared to untreated patients.19 Although the findings of these studies undeniably support the recommendation of the 2009 joint European Society of Cardiology/European Respiratory Society guide-
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lines2,3 to treat patients without Down syndrome and with Eisenmenger syndrome using advanced PAH therapies such as bosentan, the situation is not so clear in patients with Down syndrome. Owing to inherent difficulties in 6MWD testing patients with Down syndrome, we were unable to accurately assess the effects of bosentan on exercise capacity in these patients in our study. However, no safety concerns were raised in our study in treating patients with bosentan. Moreover, other studies have shown exercise capacity to be maintained9 or even improved15 in patients with PAH-CHD and Down syndrome over the mid to long term. Further investigations in this select patient population are warranted.
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11.
Acknowledgment: Medical writing support provided by Lisa Thomas, PhD (Elements Communications, Ltd., Westerham, Kent, United Kingdom) and statistical support by Jonathan Alsop, PhD (Numerus, Ltd., Sandhurst, Berkshire, United Kingdom) were funded by Actelion Pharmaceuticals. 1. Galiè N, Beghetti M, Gatzoulis MA, Granton J, Berger RM, Lauer A, Chiossi E, Landzberg M; Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 (BREATHE-5) Investigators. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation 2006;114:48 –54. 2. Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G, Rubin L, Zellweger M, Simonneau G. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2009;34:1219 –1263. 3. Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G; ESC Committee for Practice. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30:2493–2537. 4. Schulze-Neick I, Gilbert N, Ewert R, Witt C, Gruenig E, Enke B, Borst MM, Lange PE, Hoeper MM. Adult patients with congenital heart disease and pulmonary arterial hypertension: first open prospective multicenter study of bosentan therapy. Am Heart J 2005;150:716. 5. Diller GP, Dimopoulos K, Kaya MG, Harries C, Uebing A, Li W, Koltsida E, Gibbs JS, Gatzoulis MA. Long-term safety, tolerability and efficacy of bosentan in adults with pulmonary arterial hypertension associated with congenital heart disease. Heart 2007;93:974 –976. 6. Apostolopoulou SC, Manginas A, Cokkinos DV, Rammos S. Longterm oral bosentan treatment in patients with pulmonary arterial hypertension related to congenital heart disease: a 2-year study. Heart 2007;93:350 –354. 7. van Loon RL, Hoendermis ES, Duffels MG, Vonk-Noordegraaf A, Mulder BJ, Hillege HL, Berger RM. Long-term effect of bosentan in
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adults versus children with pulmonary arterial hypertension associated with systemic-to-pulmonary shunt: does the beneficial effect persist? Am Heart J 2007;154:776 –782. Durongpisitkul K, Jakrapanichakul D, Sompradikul S. A retrospective study of bosentan in pulmonary arterial hypertension associated with congenital heart disease. J Med Assoc Thai 2008;91:196 –202. Duffels MG, Vis JC, van Loon RL, Nieuwkerk PT, van Dijk AP, Hoendermis ES, de Bruin-Bon RH, Bouma BJ, Bresser P, Berger RM, Mulder BJ. Effect of bosentan on exercise capacity and quality of life in adults with pulmonary arterial hypertension associated with congenital heart disease with and without Down’s syndrome. Am J Cardiol 2009;103:1309 –1315. Kotlyar E, Sy R, Keogh AM, Kermeen F, Macdonald PS, Hayward CS, McNeil KD, Celermajer DS. Bosentan for the treatment of pulmonary arterial hypertension associated with congenital cardiac disease. Cardiol Young 2006;16:268 –274. Sitbon O, Beghetti M, Petit J, Iserin L, Humbert M, Gressin V, Simonneau G. Bosentan for the treatment of pulmonary arterial hypertension associated with congenital heart defects. Eur J Clin Invest 2006;36(suppl 3):25–31. Ibrahim R, Granton JT, Mehta S. An open-label, multicentre pilot study of bosentan in pulmonary arterial hypertension related to congenital heart disease. Can Respir J 2006;13:415– 420. D’Alto M, Vizza CD, Romeo E, Badagliacca R, Santoro G, Poscia R, Sarubbi B, Mancone M, Argiento P, Ferrante F, Russo MG, Fedele F, Calabrò R. Long term effects of bosentan treatment in adult patients with pulmonary arterial hypertension related to congenital heart disease (Eisenmenger physiology): safety, tolerability, clinical, and haemodynamic effect. Heart 2007;93:621– 625. Gatzoulis MA, Beghetti M, Galiè N, Granton J, Berger RM, Lauer A, Chiossi E, Landzberg M; BREATHE-5 Investigators. Longer-term bosentan therapy improves functional capacity in Eisenmenger syndrome: results of the BREATHE-5 open-label extension study. Int J Cardiol 2008;127:27–32. Kermeen FD, Franks C, O’Brien K, Seale H, Hall K, McNeil K, Radford D. Endothelin receptor antagonists are an effective long term treatment option in pulmonary arterial hypertension associated with congenital heart disease with or without trisomy 21. Heart Lung Circ 2010;19:595– 600. Tay EL, Peset A, Papaphylactou M, Inuzuka R, Alonso-Gonzalez R, Giannakoulas G, Tzifa A, Goletto S, Broberg C, Dimopoulos K, Gatzoulis MA. Replacement therapy for iron deficiency improves exercise capacity and quality of life in patients with cyanotic congenital heart disease and/or the Eisenmenger syndrome. Int J Cardiol 2011;149:372–376. Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF, Badesch DB, Roux S, Rainisio M, Bodin F, Rubin LJ. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001;358:1119 –1123. Galiè N, Rubin LJ, Hoeper M, Jansa P, Al-Hiti H, Meyer G, Chiossi E, Kusic-Pajic A, Simonneau G. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet 2008;371: 2093–2100. Dimopoulos K, Inuzuka R, Goletto S, Giannakoulas G, Swan L, Wort SJ, Gatzoulis MA. Improved survival among patients with Eisenmenger syndrome receiving advanced therapy for pulmonary arterial hypertension. Circulation 2010;121:20 –25.
a
Cardiovascular Research Group, School of Biomedicine, University of Manchester, Manchester, United Kingdom; bManchester Heart Centre, Manchester Royal Infirmary, Manchester, United Kingdom. Manuscript received June 9, 2011; revised manuscript received and accepted July 5, 2011. Grant support for statistical analysis of the data and writing assistance during the development of the article was provided by Actelion Pharmaceuticals, London, United Kingdom. *Corresponding author: Tel: ⫹44-161-276-8098; fax: ⫹44-161-2765138. E-mail address: [email protected] (V.S. Mahadevan). 0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2011.07.006
physiology treated with bosentan at our institution—a tertiary adult congenital cardiac center—to assess efficacy, safety, and tolerability in the medium to long term. Methods Data on all adult patients (ⱖ18 years old, with and without Down syndrome) with PAH-CHD who were referred to and received PAH therapy at our tertiary adult congenital cardiac center were prospectively collected in a dedicated database. Data recorded include patient demographics, underlying cardiac diagnoses, baseline medications, and hemodynamic, efficacy, and safety parameters. Before treatment initiation, all patients who give consent undergo right and left heart catheterization and hemodynamic parameters such as mean pulmonary arterial pressure and ratio of pulmonary to systemic pressure are measured. Where possible, exercise capacity (using the 6-minute walk distance [6MWD] test) and oxygen saturation levels at rest (using pulse oximetry or by blood sampling) are measured before bosentan initiation and subsequently at each follow-up visit. Owing to inherent difficulties in accurately assessing exercise capacity in patients with Down syndrome, 6MWD is analyzed only for patients without Down syndrome. Laboratory measurements of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and hemoglobin levels are measured before bosentan initiation and at each follow-up visit. Adverse events are recorded throughout treatment. www.ajconline.org
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Table 1 Patients’ demographics and underlying congenital heart defect Variable
Patients Without Down Syndrome (n ⫽ 29)
Patients With Down Syndrome (n ⫽ 10)
All Patients (n ⫽ 39)
40.72 ⫾ 14.25 36 (22–67) 18 (62%) 11 (38%)
32.70 ⫾ 8.06 33 (22–49) 5 (50%) 5 (50%)
38.67 ⫾ 13.32 34 (22–67) 23 (59%) 16 (41%)
Age at treatment initiation (years) Mean ⫾ SD Median (range) Women Men Race White/British Asian Other ethnic group Does not wish to state Congenital heart defect Ventricular septal defect Atrioventricular septal defect Transposition of great arteries with ventricular septal defect Secundum atrial septal defect Pulmonary atresia with or without septal defect Aortopulmonary window Patent ductus arteriosus Truncus arteriosus Tricuspid atresia
20 (69%) 5 (17%) 3 (10%) 1 (3%)
9 (90%) — — 1 (10%)
29 (74%) 5 (13%) 3 (8%) 2 (5%)
9 (31%) 2 (7%) 5* (17%) 3 (10%) 4 (14%) 2 (7%) 2 (7%) 1 (3%) 1 (3%)
3 (30%) 7 (70%) — — — — — — —
12 (31%) 9 (23%) 5* (13%) 3 (8%) 4 (10%) 2 (5%) 2 (5%) 1 (3%) 1 (3%)
* Includes 1 patient with congenitally corrected transposition of the great arteries.
All patients initiated on bosentan from October 2007 through June 2010 were included in this retrospective analysis. Data collected up to December 2010 were analyzed. Bosentan was initiated at 62.5 mg 2 times/day for the first 4 weeks and was titrated up to 125 mg 2 times/ day thereafter in all patients except 1 owing to tolerability issues. Data were analyzed using SAS 9.2 (SAS Institute, Cary, North Carolina). Patients were included in the analysis only if they had a baseline (before bosentan initiation) and ⱖ1 postbaseline (after bosentan initiation) parameter. Categorical data are described by frequency and percentage; continuous data are summarized by their mean ⫾ SD or median and range. Pretest oxygen saturation, 6MWD, AST, ALT, and hemoglobin were analyzed at all visits from baseline until treatment month 24 (i.e., baseline, months 1, 3, 6, 9, 12, 18, and 24.). Absolute and mean change from baseline values in 6MWD with no imputation for missing values and last observation carried forward (LOCF) imputation to account for missing values were analyzed. Predictors of change from baseline in 6MWD response to treatment were examined using repeated-measures multivariate linear random effects regression model, with baseline oxygen saturation, age, gender, ethnicity, and diagnosis as covariates. The same random effects models (with random intercept, slope, and quadratic terms), which does not impute for missing values or make LOCF assumptions, were also used to test for changes from baseline over time, with significance set at the p ⬍0.05 level for all parameters. Absolute pretest oxygen saturation was summarized separately for patients with and without Down syndrome with and without LOCF imputation. Changes from baseline in oxygen saturation were analyzed by a repeated-measures linear effects regression model with random intercept. The relation between change from baseline in 6MWD and oxygen saturation level was
Table 2 Baseline cardiovascular, anticoagulant, and iron-replacement medications Medications
Amiodarone Digoxin Bisoprolol Candesartan Enalapril Irbesartan Ramipril Sotalol Diltiazem Amiloride Bumetanide Co-amilofruse Eplerenone Furosemide/frusemide Spironolactone Aspirin* Clopidogrel Warfarin Atorvastatin Simvastatin Ferrous sulfate Sodium feredetate Vitamin B12 injections
Patients Without Patients With Down Syndrome Down Syndrome (n ⫽ 27) (n ⫽ 9) 1 (4%) 4 (15%) 6 (22%) 1 (4%) 2 (7%) — 2 (7%) 1 (4%) 1 (4%) — 1 (4%) 1 (4%) 2 (7%) 8 (30%) 3 (11%) 10 (37%) 1 (4%) 15 (56%) 1 (4%) 2 (7%) 4 (15%) — 1 (5%)
— — — — — 1 (11%) — 1 (11%) — 1 (11%) 1 (11%) — — 3 (33%) 1 (11%) 3 (33%) — 3 (33%) — 1 (1%) 2 (22%) 1 (11%) —
All Patients (n ⫽ 36) 1 (3%) 4 (11%) 6 (17%) 1 (3%) 2 (6%) 1 (3%) 2 (6%) 2 (6%) 1 (3%) 1 (3%) 2 (6%) 1 (3%) 2 (6%) 11 (31%) 4 (11%) 13 (36%) 1 (3%) 18 (50%) 1 (3%) 3 (8%) 6 (17%) 1 (3%) 1 (3%)
* Two patients received warfarin or clopidogrel concomitantly with aspirin.
examined for patients without Down syndrome using a graphical approach and quantified using Spearman correlation coefficient. For AST, ALT, and hemoglobin levels, data were summarized for all patients with and without LOCF imputation.
Congenital Heart Disease/Treatment Outcomes in PAH-CHD Patients
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Figure 1. Six-minute walk distance for patients without Down syndrome treated for up to 24 months with bosentan. (A) Absolute values for all patients. (B) Absolute values (mean ⫾ SD) for all patients with no imputation for missing values. (C) Absolute values (mean ⫾ SD) for all patients with last observation carried forward imputation to account for missing values. (D) Change from baseline values (mean ⫾ SD) for all patients with last observation carried forward imputation to account for missing values. CI ⫽ confidence interval.
Results The database included 39 patients with PAH-CHD, 10 of whom had Down syndrome, all having received ⱖ1 dose of bosentan. Three patients (1 with Down syndrome) were already on bosentan when referred to our center. Bosentan was initiated in all patients who were naive to other PAHspecific drugs, with the exception of 1 patient without Down syndrome who was already taking sildenafil 50 mg 3 times/ day. In all but 2 patients bosentan was maintained as monotherapy; 1 patient was also given sildenafil 16 months after starting bosentan and another was given sildenafil 2 years 2 months after starting bosentan, which was subsequently discontinued owing to poor tolerability. One patient stopped taking bosentan for 4 months after 18 months of treatment because she wanted to start a family; however, subsequent symptomatic worsening prompted a decision to restart the drug. Patient demographics are presented in Table 1. Most patients were on anticoagulant/antiplatelet therapies, principally warfarin or aspirin, and use of other cardiac drugs including  blockers, angiotensin-converting enzyme inhibitors, calcium channel blockers, and diuretic medications
was common (Table 2). Of the 8 patients on iron-replacement therapy, 6 were women. Eisenmenger syndrome was present in 35 patients (90%). Underlying congenital cardiac defects and demographics are listed in Table 1. Four patients had undergone surgical repair or palliations for the defect or its consequences (surgical repair of an atrioventricular septal defect, Mustard procedure in a patient with transposition of the great arteries with ventricular septal defect, Waterston shunt for tricuspid atresia, and stenting for pulmonary arterial stenosis in a patient with previous repair of a ventricular septal defect). Mean pulmonary arterial pressure in those who underwent cardiac catheterization before bosentan initiation was 72.3 ⫾ 18.6 mm Hg (n ⫽ 19), with a mean ratio of pulmonary to systemic pressure of 0.95 ⫾ 0.17 (range 0.48 to 1.33, n ⫽ 24). With the exception of 1 patient with Down syndrome, all patients were successfully titrated to bosentan 125 mg 2 times/day daily after 4 weeks of taking bosentan 62.5 mg 2 times/day. The patient who was initially unable to tolerate the increase in dose was successfully uptitrated to bosentan
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Figure 2. Mean oxygen saturation levels at rest before a 6-minute walk test for patients without and with Down syndrome treated for up to 24 months with bosentan. Absolute values (mean ⫾ SD) for (A) patients without Down syndrome with no imputation for missing values, (B) patients without Down syndrome with last observation carried forward imputation to account for missing values, (C) patients with Down syndrome with no imputation for missing values, and (D) patients with Down syndrome patients with last observation carried forward imputation to account for missing values. Abbreviation as in Figure 1.
125 mg 2 times/day 2 years 8 months after initiation of therapy. Mean durations of bosentan treatment from date of commencement to latest/final 6MWD test or liver function test were 2.1 ⫾ 1.5 years (median 1.7) for all patients (n ⫽ 39), 2.2 ⫾ 1.3 years (median 1.8) for patients without Down syndrome (n ⫽ 29), and 2.0 ⫾ 2.2 years (median 1.3) for patients with Down syndrome (n ⫽ 10). Individual data from patients without Down syndrome (n ⫽ 25, 4 patients excluded from analyses because baseline data were not available) showed that 6MWD improved from baseline at almost every time point (Figure 1), with mean improvements from baseline value (293 ⫾ 108 m) achieved at each time point for absolute values, absolute values for LOCF, and change from baseline values for LOCF. The postbaseline average increase in 6MWD of 54 m was highly statistically significant (p ⬍0.0001 vs no increase, random effects model). Male gender was a predictor of 6MWD response to bosentan, with men having a statistically significantly higher average increase in 6MWD of 33 m compared to women (p ⫽ 0.016, random effects model). There were no other statistically significant predictors of response among the other covariates tested including age, ethnicity,
diagnosis, and baseline oxygen saturation at rest. For patients without Down syndrome, mean pretest oxygen saturation was 84.6 ⫾ 6.0% at baseline (n ⫽ 25) and remained stable throughout treatment with bosentan (Figure 2), with no statistically significant change over time (p ⫽ 0.24, random effects linear regression model with random intercept). There was no statistically significant relation between change in 6MWD and change in oxygen saturation in this patient group (p ⫽ 0.8). Oxygen saturation levels for patients with Down syndrome also remained stable throughout bosentan treatment (Figure 2). Before bosentan treatment mean levels of AST were 27.9 ⫾ 9.5 IU (n ⫽ 34, 3 patients without Down syndrome and 2 with Down syndrome were excluded from analysis because baseline data were not available) and those of ALT were 21.9 ⫾ 8.4 IU (n ⫽ 36, 2 patients without Down syndrome and 1 with Down syndrome were excluded from analysis because baseline data were not available). There was no clinically relevant or statistically significant increase in either liver enzyme during bosentan treatment. For patients with data at month-24 levels were 24.9 ⫾ 4.5 IU (n ⫽ 13) for AST and 17.3 ⫾ 5.2 IU (n ⫽ 14) for ALT.
Congenital Heart Disease/Treatment Outcomes in PAH-CHD Patients
Month-24 LOCF values were 28.7 ⫾ 10.3 IU (n ⫽ 34) for AST and 20.7 ⫾ 8.2 IU (n ⫽ 36) for ALT. For the 2 analyses month-24 levels for these liver enzymes were within the normal range (0 to 40 for AST and 0 to 45 for ALT). Mean pretreatment baseline hemoglobin levels were 18.2 ⫾ 4.1 g/dl (n ⫽ 36, 2 patients without Down syndrome and 1 with Down syndrome were excluded from analysis because baseline data were not available) and 18.2 ⫾ 2.6 g/dl for patients with data at month 24 (n ⫽ 14) and 18.3 ⫾ 2.8 g/dl (n ⫽ 36) for month-24 LOCF. No significant changes in hemoglobin levels were observed with bosentan treatment. Twenty-two adverse events were reported in 16 patients (41%), namely headache (n ⫽ 10), lower-limb edema (n ⫽ 4), nasopharyngitis (n ⫽ 3), heavy legs (n ⫽ 2), flushing, interaction with warfarin, and itchy skin (n ⫽ 1). No patient discontinued the drug because of adverse events. Seven patients died during the follow-up period. Causes of death were stroke (n ⫽ 1), respiratory complications (n ⫽ 1), and progressive heart failure (n ⫽ 1) in the 3 patients with Down syndrome. Causes of mortality in patients without Down syndrome included sudden cardiac death (presumed arrhythmia, n ⫽ 2), cerebral abscess (n ⫽ 1), and hemoptysis (n ⫽ 1). None of these deaths were considered related to bosentan treatment in the opinion of the treating clinician. Discussion These data provide evidence that patients without Down syndrome with PAH-CHD gain long-term symptomatic benefit in exercise capacity without detrimental effects on systemic oxygen saturation after treatment with bosentan. In addition, it provides supportive evidence that bosentan is well tolerated in patients with PAH-CHD with and without Down syndrome. Retrospective analyses of small numbers of patients without Down syndrome with PAH-CHD (n ⫽ 6 to 17) previously naive to advanced PAH therapy have shown improvements in 6MWD from 34 to 142 m after 6 months of bosentan therapy8,9 and from 27 to 66 m after 15 months of therapy.10,11 Prospective open-label studies with small numbers of treatment-naive patients without Down syndrome and with PAH-CHD of around 1 year in duration have similarly found improvements in 6MWD from 34 to 74 m.4,12–14 We report a significant (p ⬎0.0001) average improvement in 6MWD of 54 m over a 2-year observation period in patients without Down syndrome with PAH-CHD. To our knowledge there are only 2 other contemporary reports, which were retrospective database analyses, of improvements in exercise capacity for up to 2 years with endothelin receptor antagonist monotherapy in patients with PAHCHD. Eighteen adult patients without Down syndrome followed up for a mean period of 29 months had a significant improvement of 124 m after 2 years of bosentan monotherapy.5 Another study of 53 patients, which included adults with and without Down syndrome (mean bosentan or sitaxsentan treatment duration of 15 months), showed a mean 88-m improvement at 2 years for all patients and a 108-m improvement in the Down syndrome patient subgroup.15
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In our study male gender was a predictor of a better response to bosentan therapy, with men having a greater increase in 6MWD than women. To the best of our knowledge, this is the first time such an observation has been reported. The reason for this is unknown. When we retrospectively examined baseline 6MWD there were no differences between men and women (295 ⫾ 126 vs 291 ⫾ 100 m, p ⫽ 0.9, Wilcoxon test). There was a significant difference in hemoglobin levels between men and women without Down syndrome at baseline (20.9 ⫾ 3.2 vs 16.3 ⫾ 3.9 g/dl, respectively, p ⫽ 0.011, Wilcoxon test), although not at the last available observation (19.9 ⫾ 2.6 vs 17.2 ⫾ 2.7 g/dl, respectively, p ⫽ 0.074, Wilcoxon test). All patients underwent baseline and 6-month checks on ferritin/ iron levels and 5 patients without Down syndrome required iron-replacement therapy. Of these patients who received iron-replacement therapy 4 were women. It has recently been shown that iron replenishment can improve exercise tolerance in patients with Eisenmenger syndrome.16 Based on this, it is clear the observed effect of a greater increase in 6MWD in men in our study is not attributable to iron therapy. However, iron reserves may be lower in women of menstruating age. In concordance with other studies of advanced therapy in PAH-CHD1,7,9,11,12,14,15 there was no change in levels of systemic oxygen saturation at rest in patients with and without Down syndrome in this study. Bosentan was well tolerated by all patients in this study. Adverse events were reported by ⬍1/2 of all patients and were typical of those observed in randomized controlled trials of bosentan.1,17,18 None of the 7 deaths were attributed to the drug but were considered owing to recognized comorbidities of CHD. No patient had increased liver enzymes in this study necessitating withdrawal of the drug, consistent with other studies in patients with PAH-CHD.4,11 Hemoglobin levels remained stable for all patients in this study. Within the recognized limitations of this being an uncontrolled retrospective analysis of data collected in a realworld clinical situation, our study substantially adds to growing evidence that advanced PAH therapies have a longterm beneficial role in the treatment of patients with PAHCHD, in particular in those with Eisenmenger syndrome. One of the principal limitations in our study is incomplete data owing to patients missing clinic visits, inability to perform the 6MWD test, or not being on therapy long enough to contribute data to each time point analyzed. However, LOCF analysis for each parameter did support the data derived from the analyses where data were missing. The BREATHE-5 randomized placebo-controlled study provided evidence of short-term improvements in hemodynamics and exercise capacity after treatment with bosentan in patients with Eisenmenger syndrome1 and its open-label extension showed these improvements lasted up to 40 weeks of treatment.14 Our study shows symptomatic benefit can be gained for periods ⬎2 years. It has recently been shown that advanced PAH therapies confer a survival advantage to patients with Eisenmenger syndrome compared to untreated patients.19 Although the findings of these studies undeniably support the recommendation of the 2009 joint European Society of Cardiology/European Respiratory Society guide-
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lines2,3 to treat patients without Down syndrome and with Eisenmenger syndrome using advanced PAH therapies such as bosentan, the situation is not so clear in patients with Down syndrome. Owing to inherent difficulties in 6MWD testing patients with Down syndrome, we were unable to accurately assess the effects of bosentan on exercise capacity in these patients in our study. However, no safety concerns were raised in our study in treating patients with bosentan. Moreover, other studies have shown exercise capacity to be maintained9 or even improved15 in patients with PAH-CHD and Down syndrome over the mid to long term. Further investigations in this select patient population are warranted.
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Acknowledgment: Medical writing support provided by Lisa Thomas, PhD (Elements Communications, Ltd., Westerham, Kent, United Kingdom) and statistical support by Jonathan Alsop, PhD (Numerus, Ltd., Sandhurst, Berkshire, United Kingdom) were funded by Actelion Pharmaceuticals. 1. Galiè N, Beghetti M, Gatzoulis MA, Granton J, Berger RM, Lauer A, Chiossi E, Landzberg M; Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 (BREATHE-5) Investigators. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation 2006;114:48 –54. 2. Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G, Rubin L, Zellweger M, Simonneau G. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2009;34:1219 –1263. 3. Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G; ESC Committee for Practice. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30:2493–2537. 4. Schulze-Neick I, Gilbert N, Ewert R, Witt C, Gruenig E, Enke B, Borst MM, Lange PE, Hoeper MM. Adult patients with congenital heart disease and pulmonary arterial hypertension: first open prospective multicenter study of bosentan therapy. Am Heart J 2005;150:716. 5. Diller GP, Dimopoulos K, Kaya MG, Harries C, Uebing A, Li W, Koltsida E, Gibbs JS, Gatzoulis MA. Long-term safety, tolerability and efficacy of bosentan in adults with pulmonary arterial hypertension associated with congenital heart disease. Heart 2007;93:974 –976. 6. Apostolopoulou SC, Manginas A, Cokkinos DV, Rammos S. Longterm oral bosentan treatment in patients with pulmonary arterial hypertension related to congenital heart disease: a 2-year study. Heart 2007;93:350 –354. 7. van Loon RL, Hoendermis ES, Duffels MG, Vonk-Noordegraaf A, Mulder BJ, Hillege HL, Berger RM. Long-term effect of bosentan in
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