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cyclins (Flolan), endothelin receptor antagonists. (bosentan) and phosphodiesterase inhibitors (Sildenafil), have substantially improved the situation ofpatients.
ORIGINAL ARTICLE

bosentan in Dutch patients with Eisenmenger syndrome: preliminary

Applicability

of

results on safety and exercise capacity

M.G.J. Duffels, R.M.F. Berger, P. Bresser, H.A.C.M. de Bruin-Bon, E. Hoendermis, B.J. Bouma, B.J.M. Mulder

Background. The purpose of this study was to investigate the applicability of bosentan treatment in a broad selection of patients with Eisenmenger syndrome. Methods. Dutch patients with Eisenmenger syndrome in New York Heart Association functional class m, 9 (41%) male and 13 (59%) female, including 11 patients with Down syndrome (50%), aged 20 to 61 years (median 37 years), were screened for an open-label, standardised treatment protocol. Patients underwent clinical xainations, six-minute walk test (6-MWT), resting oxygen saturation measurements, cardiac MRI, Doppler echocardiography, lung function tests and exercise capacity testing by peak oxygen consumption at baseline. At 12 weeks of treatment 6-MVWT and at 26 weeks 6-MWT and Doppler echocardiography were repeated. Results. Median follow-up of the patients who started bosentan treatment was five months (range 0.5 to 9.6 months). Oxygen saturation at baseline M.G.J. Duffels H.A.C.M. de Bruln-Bon B.J. Bouma B.J.M. Mulder Department of Cardiology, Academic Medical Centre, Amsterdam, the Netherlands R.M.F. Berger Department of Paediatric Cardiology, University Medical Centre Groningen, Groningen, the Netherlands P. Bresser Department of Pulmonology, Academic Medical Centre, Amsterdam, the Netherlands E. Hoendermis Department of Cardiology, University Medical Centre Groningen, Groningen, the Netherlands

Correspondence to: B.J.M. Mulder Department of Cardiology B2-240, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands E-mail: [email protected]

Netherlands Heart Journal, Volume 14, Number 5, May 2006

was 83% (range 76 to 91%) and did not decrease during treatment. Compared with baseline, 6MWT increased after 12 weeks from 333±93 m to 384±89 m. None of the patients discontinued medication and no liver finction abnormalities were observed. Of all Doppler echocardiographic and MRI parameters measured for right ventricular function, tricuspid annular peak systolic velocities using tissue Doppler imagng (TDI-S) was the only independent predictor for six-minute walk test

(P=0.8, p=0.001).

Conclusion. Bosentan may be safely applied in patients with Eisenmenger syndrome combined with complex congenital heart disease or with Down syndrome. Our preliminary results suggest that exercise tolerance improves during the first months of bosentan treatment. (Neth Heart J 2006;14:165-70.) Keywords: congenital heart disease, Eisenmenger syndrome, medical treatment The Eisenmenger syndrome may develop with systemic-to-pulmonary shunt originating from diverse uncorrected congenital heart defects. Eisenmenger syndrome is characterised by severe irreversible pulmonary arterial hypertension (PAH) and reversal of a previous systemic-to-pulmonary shunt leading to cyanosis, initially during exercise and at a later stage at rest. PAH is characterised by remodelling of the vascular wall, plexiform lesions, and pulmonary vascular obstruction leading to progressive right heart failure and death. Eisenmenger syndrome is at the severe end of the spectrum of PAH-associated with congenital heart defects. PAH-associated congenital heart defects and especially Eisenmenger syndrome carry a high risk of morbidity and mortality in a relatively young patient population with very limited treatment options. Once Eisenmenger syndrome is present surgical closure of 165

Applicability of bosentan in Dutch patients with Eisenmenger syndrome: preliminary results on safety and exercise capacity

the defect is no longer an option. Exercise tolerance in patients with PAH related to congenital heart defects is often low, even in seemingly asymptomatic patients, as self-reporting in those patients is often unreliable."2 The six-minute walk test (6-MWT) is commonly used for the assessment of submaximal exercise capacity in patients with pulmonary arterial hypertension.3 New medical treatment strategies, such as prostacyclins (Flolan), endothelin receptor antagonists (bosentan) and phosphodiesterase inhibitors (Sildenafil), have substantially improved the situation of patients with PAH. However, in patients with Eisenmenger syndrome little is known about the treatment effects of phosphodiesterase inhibitors. Prostacyclin therapy, on the other hand, is complicated by the need for continuous intravenous infusion or frequent nebulisers. In patients with idiopathic PAH or PAH associated with collagen vascular disease or HIV, bosentan has been shown to improve exercise capacity, cardiopulmonary haemodynamic variables and New York Heart Association (NYHA) functional class.46 In patients with Eisenmenger syndrome there is, however, a theoretical risk of destabilising the fine balance between the systemic and pulmonary circulation, thereby worsening right-to-left shunting and exaggerating cyanosis. Another concern with bosentan treatment is increase in liver enzymes. These liver abnormalities were reversible with dose reduction or treatment discontinuation.7 Recently, the BREATHE5 study, the first placebo-controlled study in patients with Eisenmenger syndrome, has demonstrated that oral bosentan was well-tolerated and improved exercise capacity and haemodynamics, without compromising peripheral oxygen saturation,8 during 16 weeks of follow-up. Moreover, several recently published small open-label studies have suggested benefit of bosentan in congenital heart defect patients with PAH.9-11 However, the BREATHE-5 and other recent studies applied rather strict inclusion criteria for their study populations. Patients with Down syndrome or with complex congenital heart defects (such as atrioventricular septal defect) were generally not included in these studies. Therefore, we wanted to investigate the applicability of oral bosentan treatment by a standardised treatment protocol in a broad selection of Dutch patients with Eisenmenger syndrome. Here, we report the preliminary results ofbosentan treatment on safety and the effect on exercise capacity.

syndrome. Patients could have any of the following congenital heart defects: univentricular heart, patent ductus arteriosus and septal defects such as ventricular septal defect (VSD), atrial septal defect (ASD), or atrioventricular septal defect (AVSD). Also patients with PAH as a result of surgical shunts (Potts, Waterston, Blalock-Taussig) were eligible for inclusion. Patients with right ventricular outflow tract stenosis were excluded. Patients' treatment regimens remained unchanged during the last month before enrolment in the protocol and during the study period, apart from the addition of bosentan. Patients receiving prostacyclin, glibenclamide or cyclosporin treatments were excluded from the protocol. Women of childbearing potential had to use effective contraception and have a negative pregnancy test. Study protocol This was an uncontrolled open-label study approved by the local Ethics Committee ofthe Academic Medical Centre in Amsterdam. All patients were evaluated at

Patients and methods Inclusion criteria To investigate the applicability of bosentan in a Dutch cohort ofadult patients with Eisenmenger syndrome, the Interuniversity Cardiology Institute ofthe Netherlands (ICIN) initiated a standardised and centrally directed treatment protocol in January 2005. Patients with Eisenmenger syndrome from all Dutch hospitals could be enrolled, including patients with Down

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Figure 1. Cardiac MR image, oblique sagittal view, of a patient with Eisenmenger syndrome due to a ventricular septal defect (*). Arrow indicates the right ventricular bypertropky. Note the dilated pulmonary artery (PA) with a small regurgitant jet. LV=left ventricle, RV=right ventricle.

Netherlands Heart Journal, Volume 14, Number 5, May 2006

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Applicability of bosentan in Dutch patients with Eisenmenger syndrome: preliminary results on safety and exercise capacity

Figure2B. Apicalfour-chamber view usingtisueDoppkerimaging with the sample volume at the tricuspid annulus. S-peak systolic

velocity.

Figure 2A. Apical four-chamber view at two-dimensional echocardiography of a patient with a complete atrioventricularseptal defet (*). S indicates the level ofthe tricuspid annulusfor measurement of tissue Doppler imaging peak systolic velocity. RV=right ventrice, LV=left ventricle, RA=trght atrium, LA=eft atrium.

baseline, with a comprehensive medical history, full clinical examination, laboratory tests, 6-MWT, cardiac MRI, Doppler echocardiography, maximal exercise capacity testing with peak oxygen consumption (peak VO2) and lung function tests. The 6-MWT was performed with continuous pulse oximetry monitoring.12 Patients underwent cardiac MRI for assessment ofright ventricular (RV) volumes, RV ejection fraction, and shunt measurement (figure 1). By means of Doppler echocardiography, right ventricular function was evaluated using tricuspid annular plane systolic excursions (TAPSE) and tissue Doppler imaging (TDI) was used to measure tricuspid annular peak systolic velocities (TDI-S)13 (figures 2A and B). Systolic right ventricular and pulmonary arterial pressures were estimated by means of the tricuspid regurgitation jet velocity. To exclude other causes of PAH, lung function tests (spirometry, forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC)) were

performed. At 12 weeks of treatment 6-MWT, and at 26 weeks 6-MWT and Doppler echocardiography were repeated.

(QC

Netherlands Heart Journal, Volume 14, Number 5, May 2006

After one year of treatment 6-MWT, Doppler echocardiography, MRI and peak VO2 will be re-evaluated. Oral bosentan was administered at an initial dose of 62.5 mg twice daily. Four weeks later, after measurement ofperipheral oxygen saturation and liver function tests, bosentan was increased to a maximum dose of 125 mg twice daily, if well tolerated. Treatment safety was evaluated at 12 and 26 weeks of treatment by monitoring adverse events such as flushing and nasal congestion, ECG, vital signs, pulse oximetry, and premature treatment discontinuations. Liver ftmction tests and haemoglobin levels were checked every two weeks for the first three months and monthly thereafter. According to the bosentan summary of product characteristics, the standard threshold for liver function abnormality of >3 times the upper limit of nonnal (ULN) was applied. Statistical analysis The descriptive data are presented as mean with standard deviation if normally distributed or as median with range, as appropriate. Numbers of patients were too small for statistical analysis ofthe treatment effect.

Results Patients Twenty-two patients with Eisenmenger syndrome, 9 (41%) male and 13 (59%) female, aged 20 to 61 years (median 37 years), were screened for the standardised treatment protocol between January and December 2005. Of these patients, 11 had Down syndrome. None ofthe patients had undergone previous repair of their congenital heart defect. Subsequently, 12 patients started bosentan treatment, one died prior to bosentan treatment, 2 refused treatment and 7 patients are awaiting the start of bosentan treatment. 167

Applicability of bosentan in Dutch patients with Eisenmenger syndrome: preliminary results on safety and exercise capacity

Table 1. Baseline characteristics of Eisenmenger patients (n=22). 37 (20-61) Age in years (median, range) 41 Men (%) 11 Down syndrome (n) Underlying diagnosis (n) - Atrial septal defect, sinus venosus type 2 - Ventricular septal defect 10 - Atrioventricular septal defect 8 - Univentricular heart 2 Pulmonary arterial pressure in mmHg (mean ± SD) 84±14 83±5 Oxygen saturation in % (mean ± SD)

Baseline characteristics Table 1 summarises the patients' baseline characteristics. One patient with VSD had a concurrent small secundum ASD. All patients experienced dyspnoea and impairment of exercise tolerance, and were in NYHA functional class III. Al patients were cyanotic with peripheral oxygen saturations ranging from 76 to 91% (mean 83±5%) at rest, breathing room air. Baseline systolic pulmonary arterial pressure (sPAP), assessed on the basis of echocardiographic evaluation, was significantly increased with a mean sPAP of 83.7 mmHg (±14 mmHg, range 57 to 105 mmHg). Baseline 6-MW distance was 333±93 m.

Safety and tolerability All 12 patients tolerated induction of oral bosentan therapy without any signs of decreased oxygen saturation. Patients started bosentan 125 mg twice a day after receiving bosentan 62.5 mg twice daily for four weeks. One patient died suddenly during bosentan treatment, four months after initiation, probably due to arrhythmias. None of the other 11 patients discontinued their medication and no liver function abnormalities (>3x ULN) were observed. Flushing and headache were reported occasionally but resolved within two weeks without regimen changes. One patient experienced severe throat pain and in one patient an asymptomatic increase in liver transaminases (3x ULN) was observed. Both resolved within two weeks after dose reduction, whereupon the 125 mg twice daily dose was resumed without reoccurrence of the problems. No patients required additional therapy because of progression ofdisease. Treatment effect The median follow-up ofpatients treated with bosentan was 5.0 months (range 0.5 to 9.6 months). Figure 4 depicts the changes in submaximal exercise capacity and figure 5 the changes in oxygen saturation at rest a

a 600

S: 450

At baseline, right ventricular function was evaluated by means of Doppler echocardiography, TAPSE and TDI-S, and by cardiac MRI, RV ejection fraction. TDI-S was significantly correlated with the six-minute walk test (R=0.72) and ofall RV function parameters it was the only independent predictor for six-minute walk test (P=0.8, p=0.001) (figure 3).

0

150 -

Baseline

12 weeks

26 weeks Follow-up

bosentan treatment.

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0

E 500 -

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400-

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0

3' 300 x

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Figure 4. Six-minute walk test in all individual patients with Eisenmenger syndrome at baseline, and after 12 and 26 months of

2 600-

'

Patients without Down syndrome * Patients with Down syndrome

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Figure 3. Relation between tricuspid annularpeak systolic velocity usingtissueDopplerimaging (TDI-S) andsix-minute walk test at baseline.

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Figure 5. Oxygen saturation atrestin all individualpatients with Eisenmenger syndrome, at baseline, and afterfour weeks, 12 weeks and 26 weeks of bosentan treatment.

Netherlands Heart Journal, Volume 14, Number 5, May 2006

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Applicability of bosentan in Dutch patients with Eisenmenger syndrome: preliminary results on safety and exercise capacity

o 90-

60

30-

0 Baseline

12 weeks

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Figure 6. Lowest oxygen saturation measured duringthessix-ninute walk test in patients with Eisenmenger syndrome, at baseline and during 12 and 26 weeks of bosentan treatment.

at baseline, after 12 and after 26 weeks of bosentan treatment. Compared with baseline, the distance walked in the 6-MW increased after 12 weeks from 333±93 m to 384±89 m. After 26 weeks of treatment with bosentan, mean 6-MWT distance was 367±84 m. Oxygen saturation breathing room air remained virtually unchanged compared with baseline (83±5%) after 4, 12 and 26 weeks of bosentan treatment, 86±4%, 88±4% and 85±3%, respectively. After 12 weeks of bosentan treatment, four patients reported 'feeling significantly better' during treatment, none felt worse. The lowest mean oxygen saturation levels as measured by continuous pulse oximetry performed during the 6-MWT at baseline was 62% (range 40 to 75%). At 12 and 26 weeks the levels of the lowest oxygen saturation remained virtually unchanged compared with baseline (figure 6).

Discussion Our preliminary data indicate that bosentan may be safely applied in patients with Eisenmenger syndrome combined with complex congenital heart disease or with Down syndrome. Our preliminary results suggest that exercise tolerance improves during the first months of bosentan treatment. The general safety observations in this study are in accordance with the recent studies with bosentan in patients with Eisenmenger syndrome.8"0"4 All patients tolerated bosentan therapy well. No changes in oxygen saturation were seen in our study, neither at rest nor during submaximal exercise while performing the 6MWT. This indicates that bosentan did not negatively influence the direction of the systemic-to-pulmonary shunt, for instance by decreasing systemic resistance. No patients required additional therapy for PAH. None of the patients discontinued medication as a result of side effects. The magnitude of the observed positive treatment effect of bosentan on the distance walked in the 6-MWT in our study compares well with the observations on the 6-MWT in the other studies among patients with Eisenmenger syndrome. However, qllC

Netherlands Heart Journal, Volume 14, Number 5, May 2006

because of our small sample size this study was not powered to show significance. To study the applicability of bosentan in the general population of patients with Eisenmenger syndrome, the study sample has to be representative for the general population with Eisenmenger syndrome. The wide variety of underlying congenital heart defects in the patients with Eisenmenger syndrome enrolled in our study indeed reflects their representation in the Dutch CONCOR registry'5 and is less restrictive than the groups enrolled in the BREATHE-5 and other recent studies in patients with Eisenmenger syndrome.8-10 As patients with Down syndrome frequently have congenital heart defects, it is especially important to establish the applicability of a new medical therapy in this group specifically. To our knowledge this is the first study in patients with Eisenmenger syndrome in which a large number of the study sample had Down syndrome. Bosentan treatment appeared to be safe in the subgroup ofpatients with complex congenital heart defects (univentricular heart and AVSD) and in the patients with Down syndrome. In previous studies on patients with idiopathic PAH and PAH associated with collagen vascular disease improvement offimctional class and 6-MWT has been shown to be accompanied by improved right ventricular (RV) fiinction.16 In our study, follow-up is currently too short to evaluate RV function by means of cardiac MRI or Doppler echocardiography. Ofall RV function parameters measured at baseline, TDI-S was most strongly related to 6-MWI. TDI-S is a recently defined parameter of systolic RV function in patients with heart failure. TDI-S is usually well correlated with RV ejection fraction and a value