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Safety and tolerability of bosentan in adults with Eisenmenger physiology
International Journal of Cardiology 98 (2005) 147 – 151 www.elsevier.com/locate/ijcard
Safety and tolerability of bosentan in adults with Eisenmenger physiology Michael A. Gatzoulisa,b,*, Paula Rogersa, Wei Lia,b, Carl Harriesa, Derek Cramerc, Simon Wardc, Ghada W. Mikhaila,b, J. Simon R. Gibbsa,b a
Adult Congenital Heart Program, Royal Brompton Hospital, Sydney Street, London, SW3 6NP, UK b National Heart and Lung Institute, Imperial College, London, UK c Department of Respiratory Physiology, Royal Brompton Hospital, London, UK Received 27 May 2004; received in revised form 27 July 2004; accepted 7 August 2004 Available online 15 December 2004
Abstract Background: Bosentan, a dual-endothelin receptor antagonist, is an established treatment for pulmonary arterial hypertension. We hypothesized that bosentan is safe and well tolerated in patients with Eisenmenger physiology. Methods: In this pilot open-label study, we primarily examined safety and tolerability of oral bosentan. Patients were recruited from our adult congenital heart clinic following informed consent. Baseline and 3-month assessment included WHO functional class, resting oxygen saturations, 6-min walk test, transthoracic echocardiography and respiratory mass spectrometry. Patient clinical status and liver enzymes were closely monitored throughout. Results: All 10 study patients (42F4 years; eight female) tolerated bosentan well. No major adverse events or significant liver enzyme elevations were observed. All but one patient felt better; none felt worse. Four patients experienced transient leg oedema. Resting oxygen saturations (83F5 versus 80F5%; P=0.011) and the distance travelled in the 6-min walk test (348F112 versus 249F117 m; P=0.004) increased relative to baseline. Changes in echocardiographic parameters (maximum aortic forward flow velocity 1.3F0.1 versus 1.1F0.2 ms, P=0.013; pulmonary arterial acceleration time 66F10 versus 58F12 m/s, P=0.02) and pulmonary blood flow (3.45F1.2 versus 2.58F1.0 L/ min, P=0.008) suggested improved pulmonary haemodynamics by study end. Other echocardiographic changes suggested improved right ventricular systolic function (septal amplitude 1.0 versus 1.1 cm, P=0.048; systolic tissue Doppler velocity 4.8 versus 2.3 cm s 1, P=0.002) by study end. Conclusions: Bosentan was safe and well tolerated in adults with Eisenmenger physiology both at initiation and after 3 months of oral therapy. Clinical status of patients and pulmonary haemodynamics appeared to improve, and this warrants further investigation. D 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Eisenmenger; Pulmonary hypertension; Bosentan; Endothelin antagonists
1. Introduction Congenital heart defects associated with large systemic to pulmonary shunts can lead to pulmonary vascular disease and Eisenmenger physiology, which is defined as a reversal of cardiac shunting causing chronic hypoxaemia [1]. Dyspnoea, exercise intolerance, arrhythmia and premature * Corresponding author. Adult Congenital Heart Program, Royal Brompton Hospital, Sydney Street, London, SW3 6NP, UK. Tel.: +44 20 73518602; fax: +44 20 73518629. E-mail address: [email protected] (M.A. Gatzoulis). 0167-5273/$ - see front matter D 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2004.08.025
death are common features of Eisenmenger physiology and pulmonary arterial hypertension [1–3]. Eisenmenger patients experience a poor quality of life [1,2] but are not usually considered for intravenous prostanoid treatment or as an immediate priority for heart and lung transplantation, which have both demonstrated efficacy in this setting [4–7]. This is due to the considerably longer life expectancy of patients with Eisenmenger physiology compared with those diagnosed with primary pulmonary arterial hypertension [2,7–10] and the side effects and serious complications associated with such invasive therapies [11–14]. Furthermore, continuous parenteral infusion or frequent nebulizers
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required with prostanoids may be considered less convenient than oral therapy in a congenital heart disease population requiring long-term treatment. Tissue and plasma concentrations of endothelin-1, a potent vasoconstrictor, are elevated in patients with congenital heart disease and pulmonary arterial hypertension, suggesting a potential pathogenic role for endothelin-1 in the disease process [15–18]. Endothelin-1 binds to endothelin-A and endothelin-B receptors and can cause vasoconstriction, inflammation, fibrosis and hypertrophy, further exaggerating the changes associated with pulmonary arterial hypertension [18]. Furthermore, raised endothelin-1 levels correlate with disease severity and poorer prognosis [19]. Bosentan, an orally active antagonist of both endothelin receptor subtypes, has been shown to decrease pulmonary and systemic vascular resistance, resulting in increased cardiac output, superior exercise capacity and improved functional class in patients with pulmonary arterial hypertension, primary or secondary to scleroderma [19,20]. Similarly, oral bosentan may have a role in Eisenmenger physiology as both a disease modifying therapy and a means of improving cardiopulmonary performance for a group of patients who currently have very limited therapeutic options. There is, however, a theoretical risk of destabilizing the fine balance between the systemic and pulmonary circulation in this setting, thereby worsening right-to-left shunting and exaggerating cyanosis. The aim of our openlabel pilot study was to examine the safety and tolerability of oral bosentan therapy in adult patients with Eisenmenger physiology by assessing its mid-term effects on systemic arterial oxygen saturation, exercise capacity and cardiopulmonary haemodynamics.
2. Materials and methods 2.1. Patients Active patients from the Royal Brompton Adult Congenital Heart Clinic with pulmonary arterial hypertension related to Eisenmenger physiology and nonrestrictive intracardiac communication with a right-to-left shunt at rest were enrolled in this open-label, single-arm pilot study. Informed patient’s consent was obtained prior to study entry, and the protocol was approved by the institutional ethics committee. Enrolled patients weighed N45 kg, had been in a stable condition for at least 3 months prior to study entry and were in WHO functional class III. In addition, enrolled patients had resting systemic arterial oxygen saturations of b90% and N70%—at rest in room air—and were not pregnant. 2.2. Investigations Patients were admitted to hospital for assessment at baseline (prior to initiating therapy) and after 12 weeks of
oral bosentan therapy and finally within 2 weeks of study completion for a discontinuation review. Resting systemic arterial oxygen saturation was measured indirectly by noninvasive finger pulse oximetry after 5 min absolute rest in the sitting position, and the mean of three consecutive readings was recorded for analysis. Exercise capacity was evaluated using the unencouraged 6-min walk test [21]. Systolic and diastolic blood pressures were measured using a sphygmomanometer. Right and left systolic and diastolic ventricular function was assessed by transthoracic echocardiography (Hewlett Packard, Sonos 5500 system; Andover, MA, USA). Echocardiographic measurements included transtricuspid peak early and late diastolic flow velocities (pulsed wave Doppler); tricuspid valve regurgitation (colour/continuous wave Doppler); pulmonary arterial and aortic forward flow velocities, maximum velocities, acceleration and ejection times (pulsed wave Doppler); M-mode amplitude of the septum and systolic tissue Doppler velocity of the left, septal and right atrioventricular (AV) junction. All M-mode and Doppler flow velocities were recorded digitally with a superimposed electrocardiogram (ECG) and phonocardiogram. Pulmonary blood flow were estimated by the noninvasive acetylene rebreathing method (Amis 2000, Respiratory Mass Spectrometer, Odense, Denmark) [22] and indexed for body surface area. Pulmonary function (forced expiratory volume in 1 s; forced vital capacity) were assessed by spirometry. Analyses of echocardiographic, pulmonary blood flow and pulmonary function data were made blindly from the clinical data. Oral bosentan was administered at an initial dose of 31.25 mg and was up-titrated slowly to a hospital discharge dose of 62.5 mg BID under frequent monitoring of heart rate, blood pressure and resting systemic arterial oxygen saturation. Four weeks later, bosentan was increased to a maximum dose of 125 mg BID (last five patients) to study end if tolerated well. Physical examination, vital signs and clinical laboratory tests, including haemoglobin, haematocrit and liver function tests (AST/ALT) were performed monthly or whenever was indicated by the patients’ clinical status. 2.3. Statistical analysis Treatment-related changes in safety variables from baseline to 12 weeks were compared using the Student’s twotailed paired t-test.
3. Results Ten patients with Eisenmenger physiology (eight female; mean age 42F4 years) with large nonrestrictive ventricular septal defects were enrolled in the study. All patients tolerated induction of oral bosentan therapy without systemic compromise or drop in resting systemic arterial
M.A. Gatzoulis et al. / International Journal of Cardiology 98 (2005) 147–151
oxygen saturation. Five patients received bosentan 125 mg BID, however, one experienced dizziness and was downtitrated to 62.5 mg BID. There were no deaths, and no patient required additional disease-targeted therapy for pulmonary arterial hypertension. Nine patients felt better, none felt worse. Mean resting systemic arterial oxygen saturation levels, 6-min walk test distances, pulmonary blood flow and index and several echocardiographic parameters (pulmonary arterial acceleration/ejection time, maximum aortic forward flow velocity, septal amplitude and systolic tissue Doppler velocity) increased significantly at study end compared with baseline
149
(Fig. 1A/B; Table 1). Both the resting systemic arterial oxygen saturation mean (Fig. 1A) and the mean distance travelled in metres during the 6-min walk test (Fig. 1B) at the discontinuation review (9F3 days) remained increased compared to baseline. There were no significant changes in heart rate, blood pressure (Table 1), oxygen consumption (265.5 versus 203.3; P=0.24) or lung function (forced expiratory volume in 1 s: 63.0 versus 64.8, P=0.34; forced vital capacity: 74.2 versus 74.5, P=0.92) at 12 weeks relative to baseline. Furthermore, haemoglobin levels and liver enzymes remained unchanged. Four patients experienced transient
Fig. 1. (A) Mean (FS.E.M.) resting systemic arterial oxygen saturations and (B) mean (FS.E.M.) 6-min walk test results at baseline, 12 weeks and 9F3 days after discontinuation of bosentan treatment.
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Table 1 Functional, haemodynamic and echocardiographic findings at baseline and after 12 weeks of treatment Parameter
N
Mean (FS.D.) at baseline
Mean (FS.D.) 12 weeks
P
BP systolic, mm Hg BP diastolic, mm Hg Heart rate, bpm Haemoglobin, g/dL MCV, fL Pulmonary blood flow, L min 1 Pulmonary blood flow index, Lmin 1 m 2 RV-RA pressure gradient, mmHg V max AO m s 1 V max PA m s 1 PA-ACT, ms PA-ET, ms Septal amplitude, cm S-TDI, cm s 1
10
121 (10)
116 (15)
0.278
10
74 (10)
67 (12)
0.214
10 10
75 (11) 20.2 (2.2)
76 (13) 20.1 (2.6)
0.841 0.798
10 6
88.4 (5.4) 2.6 (1.0)
88.3 (7.8) 3.4 (1.2)
0.937 0.008
6
1.6 (0.4)
2.1 (0.55)
0.007
10
106 (14)
78 (7)
0.018
10 10 10 10 10 10
1.1 0.8 58 127 1.0 4.8
(0.2) (0.3) (3) (15) (0.3) (1.7)
1.3 1.2 68 198 1.1 7.1
(0.15) (0.2) (5) (39) (0.2) (2.3)
0.003 0.266 0.021 0.009 0.048 0.002
PA—pulmonary arterial; AO—aortic; V max—maximum flow velocity; ACT—acceleration time; ET—ejection time; S-TDI—systolic tissue Doppler velocity.
leg oedema during the first month’s treatment, but no major adverse events were observed. There was no apparent dosedependent effect of bosentan for any variables measured. Nine out of the 10 patients went on compassionate openlabel extension bosentan therapy after the discontinuation review.
4. Discussion Our study suggests that oral bosentan is safe and well tolerated by patients with Eisenmenger physiology, and it does not cause any worsening of right-to-left shunting (a potential risk of vasodilatory treatment in these patients). Due to its demonstrated ability to improve cardiopulmonary haemodynamics and exercise capacity in other patient groups with pulmonary arterial hypertension, bosentan has an obvious potential value and needs to be considered for patients with Eisenmenger physiology. These patients currently have rather limited therapeutic options. Heart and lung transplantation is cumbersome and may not convey clear survival benefits as Eisenmenger patients often survive to the fourth or fifth decade without surgery[2,8,9] by which time they cease to be transplant candidates. Continuous parenteral infusion or intermittent nebulized administration of prostanoids has been shown to improve haemodynamics in patients with Eisenmenger physiology [23,24]. However, an effective and well-tolerated oral therapy would offer greater convenience and possibly be more acceptable than prostanoids for patients
with congenital heart disease, likely to require very long term therapy. Oral therapy would, therefore, convey a major advantage particularly for this patient population. We did not see detrimental falls in systemic resistance sufficient to result in increased right-to-left shunting and reduced systemic arterial oxygen saturation in this study, either at induction or during the 12 weeks of bosentan therapy. Although our data indicate a fall in both pulmonary and systemic pressures, albeit not significant, there was no disruption of the fine equilibrium between the systemic and pulmonary circulations; hence, systemic oxygen saturations did not fall. Of note, there was no rise in liver enzymes or other major side effects associated with bosentan therapy. These observations are reassuring because adults with Eisenmenger physiology typically have multiorgan involvement and are, therefore, potentially at greater risk of liver or other organ dysfunction. Furthermore, our preliminary data suggest that prolonged hospitalization for initiation and slow up-titration of bosentan therapy in adults with Eisenmenger physiology is unnecessary. Accordingly, we have altered our protocol to a day case approach for induction of bosentan therapy for these patients. The magnitude of the observed improvements in 6-min walking test distances (mean increase to 152% of baseline levels at 12 weeks) would likely improve quality of life and possibly prognosis for Eisenmenger physiology patients, as it has in other patient groups [19,20]. However, a larger randomized trial will be required to confirm these potential benefits of bosentan therapy. The apparent improvement in exercise capacity associated with bosentan could be attributed to increased tissue oxygen delivery secondary to reduced right-to-left shunting and augmented pulmonary blood flow, as suggested by the observed increase in resting systemic arterial oxygen saturations. However, a training effect cannot be excluded. Nevertheless, because of the clinical improvement observed and the lack of serious or persisting side effects in our pilot study, nine of the 10 patients were enrolled into an open-label bosentan therapy extension. The observed improvement in pulmonary blood flow in this study may be of theoretical concern as volume and pressure overload have been the primary predisposing factors for the development of pulmonary arterial hypertension and Eisenmenger physiology in the first place [1,2,25,26]. However, the magnitude of pulmonary blood flow at the end of the study remained relatively low (Qp:Qsb1) despite the observed increase after bosentan therapy. This is particularly so when compared with the excessive pulmonary blood flow that these patients were subjected to in early childhood [1,26]. Furthermore, the observed increases in important echocardiographic parameters (pulmonary arterial acceleration/ejection time, maximum aortic forward flow velocity) would suggest reduced resistance of the pulmonary vascular bed after 12 weeks of bosentan therapy. In addition, there was some echocardiographic evidence of a reverse right ventricular remodelling
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mechanism (increased septal amplitude and systolic tissue Doppler velocity), potentially leading to improved right ventricular performance. If larger, double-blind controlled studies confirm our early observations, such a diseasemodifying effect combined with its convenient oral route of administration would make bosentan a potential treatment for Eisenmenger physiology patients, which may have prognostic implications. Although promising, the present study is limited by its open-label design, the small number of patients recruited and by the noninvasive techniques utilized to estimate resting systemic arterial oxygen saturations and cardiac output. An ongoing large multicentre, randomized, doubleblind, placebo-controlled study evaluating a larger cohort of Eisenmenger physiology patients and utilizing haemodynamic measurements via cardiac catheterization may cast further light on the role of bosentan and its potential for ventricular remodelling in these patients. In conclusion, this pilot study demonstrated that bosentan is safe and well tolerated in adults with Eisenmenger physiology both at initiation and after 3 months of oral therapy. Furthermore, clinical status of patients and pulmonary haemodynamics appeared to improve, and this warrants further investigation.
Acknowledgements We thank Professors Timothy Evans and Martin Wilkins for their comments during the planning phase of the study, Actelion UK for providing us bosentan for the study and Tom Lucas for his undivided administrative support. Dr. Gatzoulis and the Royal Brompton Adult Congenital Heart Program are supported by the British Heart Foundation.
References [1] Wood P. The Eisenmenger syndrome: or pulmonary hypertension with reverse shunt. Br Med J 1958;2:701 – 9. [2] Daliento L, Somerville J, Presbitero P, et al. Eisenmenger syndrome. Factors relating to deterioration and death. Eur Heart J 1998;19: 1845 – 55. [3] Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997; 336:111 – 7. [4] British Cardiac Society Guidelines and Medical Practice Committee. Recommendations on the management of pulmonary hypertension in clinical practice. Heart 2001;86(Suppl. 1):i1 – 13. [5] Trulock EP. Lung transplantation for primary pulmonary hypertension. Clin Chest Med 2001;22:583 – 93. [6] Fernandes SM, Newburger JW, Lang P, et al. Usefulness of epoprostenol therapy in the severely ill adolescent/adult with Eisenmenger physiology. Am J Cardiol 2003;91:46 – 9.
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[7] Sharples L, Belcher C, Dennis C, Higenbottam T, Wallwork J. Who waits longest for heart and lung transplantation? J Heart Lung Transplant 1994;13:282 – 91. [8] Vongpatanasin W, Brickner ME, Hillis LD, Lange RA. The Eisenmenger syndrome in adults. Ann Intern Med 1998;128:745 – 55. [9] Saha A, Balakrishnan K, Jaiswal P, et al. Prognosis for patients with Eisenmenger syndrome of various aetiology. Int J Cardiol 1994;45: 199 – 207. [10] D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med 1991;115:343 – 9. [11] Paramothayan NS, Lasserson TJ, Wells AU, Walters EH. Prostacyclin for pulmonary hypertension. Cochrane Database Syst Rev 2003; CD002994. [12] Pickles H, O’Grady J. Side effects occurring during administration of epoprostanol (prostacyclin, PGI2), in man. Br J Clin Pharmacol 1982;14:177 – 85. [13] Sarris GE, Smith JA, Shumway NE, et al. Long-term results of combined heart-lung transplantation: the Stanford experience. J Heart Lung Transplant 1994;13:940 – 9. [14] Reichart B, Vosloo S, Holl J. Surgical management of heart–lung transplantation. Ann Thorac Surg 1990;49:333 – 40. [15] Adatia I, Haworth SG. Circulating endothelin in children with congenital heart disease. Br Heart J 1993;69:233 – 6. [16] Bando K, Vijayaraghavan P, Turrentine MW, et al. Dynamic changes of endothelin-1, nitric oxide, and cyclic GMP in patients with congenital heart disease. Circulation 1997;96:346 – 51. [17] Yoshibayashi M, Nishioka K, Nakao K, et al. Plasma endothelin concentrations in patients with pulmonary hypertension associated with congenital heart defects. Evidence for increased production of endothelin in pulmonary circulation. Circulation 1991;84:2280 – 5. [18] Bolger AP, Sharma R, Li W, Leenarts M, et al. Neurohormonal activation in adults with congenital heart disease: evidence of the chronic heart failure syndrome. Circulation 2002;106:92 – 9. [19] Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001; 358:1119 – 23. [20] Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896 – 903. [21] Guyatt GH, Sullivan MJ, Thompson PJ, et al. The 6-minute walk: a new measure of exercise capacity in patients with chronic heart failure. Can Med Assoc J 1985;132:919 – 23. [22] Hoeper MM, Maier R, Tongers J, et al. Determination of cardiac output by the Fick method, thermodilution, and acetylene rebreathing in pulmonary hypertension. Am J Respir Crit Care Med 1999; 180:535 – 41. [23] Rosenzweig EB, Kerstein D, Barst RJ. Long-term prostacyclin for pulmonary hypertension with associated congenital heart defects. Circulation 1999;99:1858 – 65. [24] Fernandes SM, Newburger JW, Lang P, et al. Usefulness of epoprostenol therapy in the severely ill adolescent/adult with Eisenmenger physiology. Am J Cardiol 2003;91:632 – 5. [25] Widlitz A, Barst RJ. Pulmonary arterial hypertension in children. Eur Respir J 2003;21:155 – 76. [26] Oechslin E. Eisenmenger’s syndrome. In: Gatzoulis MA, Webb GD, Daubeney P, editors. Diagnosis and management of adult congenital heart disease. Philadelphia7 Churchill Livingstone; 2003. p. 363 – 78.
Safety and tolerability of bosentan in adults with Eisenmenger physiology Michael A. Gatzoulisa,b,*, Paula Rogersa, Wei Lia,b, Carl Harriesa, Derek Cramerc, Simon Wardc, Ghada W. Mikhaila,b, J. Simon R. Gibbsa,b a
Adult Congenital Heart Program, Royal Brompton Hospital, Sydney Street, London, SW3 6NP, UK b National Heart and Lung Institute, Imperial College, London, UK c Department of Respiratory Physiology, Royal Brompton Hospital, London, UK Received 27 May 2004; received in revised form 27 July 2004; accepted 7 August 2004 Available online 15 December 2004
Abstract Background: Bosentan, a dual-endothelin receptor antagonist, is an established treatment for pulmonary arterial hypertension. We hypothesized that bosentan is safe and well tolerated in patients with Eisenmenger physiology. Methods: In this pilot open-label study, we primarily examined safety and tolerability of oral bosentan. Patients were recruited from our adult congenital heart clinic following informed consent. Baseline and 3-month assessment included WHO functional class, resting oxygen saturations, 6-min walk test, transthoracic echocardiography and respiratory mass spectrometry. Patient clinical status and liver enzymes were closely monitored throughout. Results: All 10 study patients (42F4 years; eight female) tolerated bosentan well. No major adverse events or significant liver enzyme elevations were observed. All but one patient felt better; none felt worse. Four patients experienced transient leg oedema. Resting oxygen saturations (83F5 versus 80F5%; P=0.011) and the distance travelled in the 6-min walk test (348F112 versus 249F117 m; P=0.004) increased relative to baseline. Changes in echocardiographic parameters (maximum aortic forward flow velocity 1.3F0.1 versus 1.1F0.2 ms, P=0.013; pulmonary arterial acceleration time 66F10 versus 58F12 m/s, P=0.02) and pulmonary blood flow (3.45F1.2 versus 2.58F1.0 L/ min, P=0.008) suggested improved pulmonary haemodynamics by study end. Other echocardiographic changes suggested improved right ventricular systolic function (septal amplitude 1.0 versus 1.1 cm, P=0.048; systolic tissue Doppler velocity 4.8 versus 2.3 cm s 1, P=0.002) by study end. Conclusions: Bosentan was safe and well tolerated in adults with Eisenmenger physiology both at initiation and after 3 months of oral therapy. Clinical status of patients and pulmonary haemodynamics appeared to improve, and this warrants further investigation. D 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Eisenmenger; Pulmonary hypertension; Bosentan; Endothelin antagonists
1. Introduction Congenital heart defects associated with large systemic to pulmonary shunts can lead to pulmonary vascular disease and Eisenmenger physiology, which is defined as a reversal of cardiac shunting causing chronic hypoxaemia [1]. Dyspnoea, exercise intolerance, arrhythmia and premature * Corresponding author. Adult Congenital Heart Program, Royal Brompton Hospital, Sydney Street, London, SW3 6NP, UK. Tel.: +44 20 73518602; fax: +44 20 73518629. E-mail address: [email protected] (M.A. Gatzoulis). 0167-5273/$ - see front matter D 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2004.08.025
death are common features of Eisenmenger physiology and pulmonary arterial hypertension [1–3]. Eisenmenger patients experience a poor quality of life [1,2] but are not usually considered for intravenous prostanoid treatment or as an immediate priority for heart and lung transplantation, which have both demonstrated efficacy in this setting [4–7]. This is due to the considerably longer life expectancy of patients with Eisenmenger physiology compared with those diagnosed with primary pulmonary arterial hypertension [2,7–10] and the side effects and serious complications associated with such invasive therapies [11–14]. Furthermore, continuous parenteral infusion or frequent nebulizers
148
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required with prostanoids may be considered less convenient than oral therapy in a congenital heart disease population requiring long-term treatment. Tissue and plasma concentrations of endothelin-1, a potent vasoconstrictor, are elevated in patients with congenital heart disease and pulmonary arterial hypertension, suggesting a potential pathogenic role for endothelin-1 in the disease process [15–18]. Endothelin-1 binds to endothelin-A and endothelin-B receptors and can cause vasoconstriction, inflammation, fibrosis and hypertrophy, further exaggerating the changes associated with pulmonary arterial hypertension [18]. Furthermore, raised endothelin-1 levels correlate with disease severity and poorer prognosis [19]. Bosentan, an orally active antagonist of both endothelin receptor subtypes, has been shown to decrease pulmonary and systemic vascular resistance, resulting in increased cardiac output, superior exercise capacity and improved functional class in patients with pulmonary arterial hypertension, primary or secondary to scleroderma [19,20]. Similarly, oral bosentan may have a role in Eisenmenger physiology as both a disease modifying therapy and a means of improving cardiopulmonary performance for a group of patients who currently have very limited therapeutic options. There is, however, a theoretical risk of destabilizing the fine balance between the systemic and pulmonary circulation in this setting, thereby worsening right-to-left shunting and exaggerating cyanosis. The aim of our openlabel pilot study was to examine the safety and tolerability of oral bosentan therapy in adult patients with Eisenmenger physiology by assessing its mid-term effects on systemic arterial oxygen saturation, exercise capacity and cardiopulmonary haemodynamics.
2. Materials and methods 2.1. Patients Active patients from the Royal Brompton Adult Congenital Heart Clinic with pulmonary arterial hypertension related to Eisenmenger physiology and nonrestrictive intracardiac communication with a right-to-left shunt at rest were enrolled in this open-label, single-arm pilot study. Informed patient’s consent was obtained prior to study entry, and the protocol was approved by the institutional ethics committee. Enrolled patients weighed N45 kg, had been in a stable condition for at least 3 months prior to study entry and were in WHO functional class III. In addition, enrolled patients had resting systemic arterial oxygen saturations of b90% and N70%—at rest in room air—and were not pregnant. 2.2. Investigations Patients were admitted to hospital for assessment at baseline (prior to initiating therapy) and after 12 weeks of
oral bosentan therapy and finally within 2 weeks of study completion for a discontinuation review. Resting systemic arterial oxygen saturation was measured indirectly by noninvasive finger pulse oximetry after 5 min absolute rest in the sitting position, and the mean of three consecutive readings was recorded for analysis. Exercise capacity was evaluated using the unencouraged 6-min walk test [21]. Systolic and diastolic blood pressures were measured using a sphygmomanometer. Right and left systolic and diastolic ventricular function was assessed by transthoracic echocardiography (Hewlett Packard, Sonos 5500 system; Andover, MA, USA). Echocardiographic measurements included transtricuspid peak early and late diastolic flow velocities (pulsed wave Doppler); tricuspid valve regurgitation (colour/continuous wave Doppler); pulmonary arterial and aortic forward flow velocities, maximum velocities, acceleration and ejection times (pulsed wave Doppler); M-mode amplitude of the septum and systolic tissue Doppler velocity of the left, septal and right atrioventricular (AV) junction. All M-mode and Doppler flow velocities were recorded digitally with a superimposed electrocardiogram (ECG) and phonocardiogram. Pulmonary blood flow were estimated by the noninvasive acetylene rebreathing method (Amis 2000, Respiratory Mass Spectrometer, Odense, Denmark) [22] and indexed for body surface area. Pulmonary function (forced expiratory volume in 1 s; forced vital capacity) were assessed by spirometry. Analyses of echocardiographic, pulmonary blood flow and pulmonary function data were made blindly from the clinical data. Oral bosentan was administered at an initial dose of 31.25 mg and was up-titrated slowly to a hospital discharge dose of 62.5 mg BID under frequent monitoring of heart rate, blood pressure and resting systemic arterial oxygen saturation. Four weeks later, bosentan was increased to a maximum dose of 125 mg BID (last five patients) to study end if tolerated well. Physical examination, vital signs and clinical laboratory tests, including haemoglobin, haematocrit and liver function tests (AST/ALT) were performed monthly or whenever was indicated by the patients’ clinical status. 2.3. Statistical analysis Treatment-related changes in safety variables from baseline to 12 weeks were compared using the Student’s twotailed paired t-test.
3. Results Ten patients with Eisenmenger physiology (eight female; mean age 42F4 years) with large nonrestrictive ventricular septal defects were enrolled in the study. All patients tolerated induction of oral bosentan therapy without systemic compromise or drop in resting systemic arterial
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oxygen saturation. Five patients received bosentan 125 mg BID, however, one experienced dizziness and was downtitrated to 62.5 mg BID. There were no deaths, and no patient required additional disease-targeted therapy for pulmonary arterial hypertension. Nine patients felt better, none felt worse. Mean resting systemic arterial oxygen saturation levels, 6-min walk test distances, pulmonary blood flow and index and several echocardiographic parameters (pulmonary arterial acceleration/ejection time, maximum aortic forward flow velocity, septal amplitude and systolic tissue Doppler velocity) increased significantly at study end compared with baseline
149
(Fig. 1A/B; Table 1). Both the resting systemic arterial oxygen saturation mean (Fig. 1A) and the mean distance travelled in metres during the 6-min walk test (Fig. 1B) at the discontinuation review (9F3 days) remained increased compared to baseline. There were no significant changes in heart rate, blood pressure (Table 1), oxygen consumption (265.5 versus 203.3; P=0.24) or lung function (forced expiratory volume in 1 s: 63.0 versus 64.8, P=0.34; forced vital capacity: 74.2 versus 74.5, P=0.92) at 12 weeks relative to baseline. Furthermore, haemoglobin levels and liver enzymes remained unchanged. Four patients experienced transient
Fig. 1. (A) Mean (FS.E.M.) resting systemic arterial oxygen saturations and (B) mean (FS.E.M.) 6-min walk test results at baseline, 12 weeks and 9F3 days after discontinuation of bosentan treatment.
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Table 1 Functional, haemodynamic and echocardiographic findings at baseline and after 12 weeks of treatment Parameter
N
Mean (FS.D.) at baseline
Mean (FS.D.) 12 weeks
P
BP systolic, mm Hg BP diastolic, mm Hg Heart rate, bpm Haemoglobin, g/dL MCV, fL Pulmonary blood flow, L min 1 Pulmonary blood flow index, Lmin 1 m 2 RV-RA pressure gradient, mmHg V max AO m s 1 V max PA m s 1 PA-ACT, ms PA-ET, ms Septal amplitude, cm S-TDI, cm s 1
10
121 (10)
116 (15)
0.278
10
74 (10)
67 (12)
0.214
10 10
75 (11) 20.2 (2.2)
76 (13) 20.1 (2.6)
0.841 0.798
10 6
88.4 (5.4) 2.6 (1.0)
88.3 (7.8) 3.4 (1.2)
0.937 0.008
6
1.6 (0.4)
2.1 (0.55)
0.007
10
106 (14)
78 (7)
0.018
10 10 10 10 10 10
1.1 0.8 58 127 1.0 4.8
(0.2) (0.3) (3) (15) (0.3) (1.7)
1.3 1.2 68 198 1.1 7.1
(0.15) (0.2) (5) (39) (0.2) (2.3)
0.003 0.266 0.021 0.009 0.048 0.002
PA—pulmonary arterial; AO—aortic; V max—maximum flow velocity; ACT—acceleration time; ET—ejection time; S-TDI—systolic tissue Doppler velocity.
leg oedema during the first month’s treatment, but no major adverse events were observed. There was no apparent dosedependent effect of bosentan for any variables measured. Nine out of the 10 patients went on compassionate openlabel extension bosentan therapy after the discontinuation review.
4. Discussion Our study suggests that oral bosentan is safe and well tolerated by patients with Eisenmenger physiology, and it does not cause any worsening of right-to-left shunting (a potential risk of vasodilatory treatment in these patients). Due to its demonstrated ability to improve cardiopulmonary haemodynamics and exercise capacity in other patient groups with pulmonary arterial hypertension, bosentan has an obvious potential value and needs to be considered for patients with Eisenmenger physiology. These patients currently have rather limited therapeutic options. Heart and lung transplantation is cumbersome and may not convey clear survival benefits as Eisenmenger patients often survive to the fourth or fifth decade without surgery[2,8,9] by which time they cease to be transplant candidates. Continuous parenteral infusion or intermittent nebulized administration of prostanoids has been shown to improve haemodynamics in patients with Eisenmenger physiology [23,24]. However, an effective and well-tolerated oral therapy would offer greater convenience and possibly be more acceptable than prostanoids for patients
with congenital heart disease, likely to require very long term therapy. Oral therapy would, therefore, convey a major advantage particularly for this patient population. We did not see detrimental falls in systemic resistance sufficient to result in increased right-to-left shunting and reduced systemic arterial oxygen saturation in this study, either at induction or during the 12 weeks of bosentan therapy. Although our data indicate a fall in both pulmonary and systemic pressures, albeit not significant, there was no disruption of the fine equilibrium between the systemic and pulmonary circulations; hence, systemic oxygen saturations did not fall. Of note, there was no rise in liver enzymes or other major side effects associated with bosentan therapy. These observations are reassuring because adults with Eisenmenger physiology typically have multiorgan involvement and are, therefore, potentially at greater risk of liver or other organ dysfunction. Furthermore, our preliminary data suggest that prolonged hospitalization for initiation and slow up-titration of bosentan therapy in adults with Eisenmenger physiology is unnecessary. Accordingly, we have altered our protocol to a day case approach for induction of bosentan therapy for these patients. The magnitude of the observed improvements in 6-min walking test distances (mean increase to 152% of baseline levels at 12 weeks) would likely improve quality of life and possibly prognosis for Eisenmenger physiology patients, as it has in other patient groups [19,20]. However, a larger randomized trial will be required to confirm these potential benefits of bosentan therapy. The apparent improvement in exercise capacity associated with bosentan could be attributed to increased tissue oxygen delivery secondary to reduced right-to-left shunting and augmented pulmonary blood flow, as suggested by the observed increase in resting systemic arterial oxygen saturations. However, a training effect cannot be excluded. Nevertheless, because of the clinical improvement observed and the lack of serious or persisting side effects in our pilot study, nine of the 10 patients were enrolled into an open-label bosentan therapy extension. The observed improvement in pulmonary blood flow in this study may be of theoretical concern as volume and pressure overload have been the primary predisposing factors for the development of pulmonary arterial hypertension and Eisenmenger physiology in the first place [1,2,25,26]. However, the magnitude of pulmonary blood flow at the end of the study remained relatively low (Qp:Qsb1) despite the observed increase after bosentan therapy. This is particularly so when compared with the excessive pulmonary blood flow that these patients were subjected to in early childhood [1,26]. Furthermore, the observed increases in important echocardiographic parameters (pulmonary arterial acceleration/ejection time, maximum aortic forward flow velocity) would suggest reduced resistance of the pulmonary vascular bed after 12 weeks of bosentan therapy. In addition, there was some echocardiographic evidence of a reverse right ventricular remodelling
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mechanism (increased septal amplitude and systolic tissue Doppler velocity), potentially leading to improved right ventricular performance. If larger, double-blind controlled studies confirm our early observations, such a diseasemodifying effect combined with its convenient oral route of administration would make bosentan a potential treatment for Eisenmenger physiology patients, which may have prognostic implications. Although promising, the present study is limited by its open-label design, the small number of patients recruited and by the noninvasive techniques utilized to estimate resting systemic arterial oxygen saturations and cardiac output. An ongoing large multicentre, randomized, doubleblind, placebo-controlled study evaluating a larger cohort of Eisenmenger physiology patients and utilizing haemodynamic measurements via cardiac catheterization may cast further light on the role of bosentan and its potential for ventricular remodelling in these patients. In conclusion, this pilot study demonstrated that bosentan is safe and well tolerated in adults with Eisenmenger physiology both at initiation and after 3 months of oral therapy. Furthermore, clinical status of patients and pulmonary haemodynamics appeared to improve, and this warrants further investigation.
Acknowledgements We thank Professors Timothy Evans and Martin Wilkins for their comments during the planning phase of the study, Actelion UK for providing us bosentan for the study and Tom Lucas for his undivided administrative support. Dr. Gatzoulis and the Royal Brompton Adult Congenital Heart Program are supported by the British Heart Foundation.
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