Safety and tolerability of bosentan in adults with Eisenmenger physiology
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 death are common features of Eisenmenger physiology and pulmonary arterial hypertension [1], [2], [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], [5], [6], [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], [8], [9], [10] and the side effects and serious complications associated with such invasive therapies [11], [12], [13], [14]. Furthermore, continuous parenteral infusion or frequent nebulizers 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], [16], [17], [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 open-label 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.
Section snippets
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 >45 kg, had been in a stable condition for at least 3 months
Results
Ten patients with Eisenmenger physiology (eight female; mean age 42±4 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 oxygen saturation. Five patients received bosentan 125 mg BID, however, one experienced dizziness and was down-titrated to 62.5 mg BID.
There were no deaths, and no patient required additional disease-targeted therapy
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.
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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