Endothelin receptor antagonism
improving outcomes in pulmonary
arterial hypertension Munich, 31 August 2004 In this satellite symposium, organised by Actelion Pharmaceuticals and chaired by N. Galie (Bologna, Italy) and L.J. Rubin (La Jolla, US), the rationale behind endothelin receptor antagonism treatment with bosentan, the results ofclinical trials with this treatment option for patients with pulmonary arterial hypertension and recommendations for making therapeutic choices were presented. The first speaker, V. Richard (Rouen, France), presented the rationale behind endothelin receptor antagonism treatment in pulmonary arterial hypertension. Endothelin is a regulatory peptide which is produced by vascular endothelial cells at low levels in healthy individuals. In pulmonary arterial hypertension, endothelin concentration is increased after stimulation of the endothelin system. ET-A receptors (present on smooth muscle cells and fibroblasts) and ET-B receptors (present on smooth muscle cells, fibroblasts, endothelial cells and macrophages) are considered the primary receptors of endothelin. Stimulation of receptors on smooth muscle cells leads to contraction and proliferation, and stimulation of receptors on fibroblasts leads to fibrosis. However, stimulation of ET-B on the endothelium leads to relaxation of the cell, an inflammatory response and a downregulation of endothelin. Due to endothelial dysfunction, synthesis of endothelin is, however, increased
and ET-B receptors are downregulated on endothelial cells and upregulated on smooth muscle cells, which results in increased vasoconstriction and decreased pulmonary clearance. The combined effects ofincreased endothelin concentration include pulmonary vasoconstriction, proliferation of vascular smooth muscle cells, fibrosis (proliferation of fibroblasts and production of extracellular matrix), and inflammation. Furthermore, increased endothelin concentration induces hypertrophy of the cardiac and vascular cells. Pulmonary arterial hypertension is characterised by fibrosis and hypertrophy of the pulmonary arterioles, which results in increased pulmonary vascular resistance. In an animal model of chronic overcirculation induced pulmonary arterial hypertension it was suggested that activation of the endothelin system played a major role in pulmonary arterial hypertension initiation. In patients with pulmonary arterial hypertension, overexpression of endothelin has been observed and the degree of overexpression correlated with the degree of pulmonary vascular resistance. In patients with idiopathic pulmonary arterial hypertension, endothelin levels were related to disease severity and prognosis in these patients. Also, in patients with T. Oosterhof Academic Medical Centre, Amsterdam E-mail: [email protected]
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congenital heart disease and increased pulmonary blood flow, increased levels of endothelin were found. Finally, animal models, in which oral, dual endothelin receptor blockade by bosentan prevented the increase in pulmonary vascular resistance, further support the importance of endothelin in the pathogenesis of pulmonary arterial hypertension. From animal models, it appears that dual blockade is superior to ET-A selective blockade in terms ofventricular hypertrophy and survival (Jasmin, Circulation 2001).
L.J. Rubin (La Jolla, US) gave the second presentation on bosentan and setting standards in pulmonary arterial hypertension. Pulmonary arterial hypertension can be divided into three major categories: 1. idiopathic pulmonary arterial hypertension, 2. familial pulmonary arterial hypertension, 3. pulmonary arterial hypertension related to associated disease (scleroderma, congenital heart disease, HIV infection and portal hypertension). Incidence of idiopathic pulmonary arterial hypertension is one to two per million and mostly occurs in patients aged 20 to 40 years. The natural history of patients with symptomatic idiopathic pulmonary arterial hypertension is poor. Median survival in non-treated patients is 2-3 years from the time of diagnosis. In several studies the importance of increased endothelin levels on disease severity in patients with pulmonary arterial hyper41
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tension has been shown. Furthermore in several clinical trials the efficacy and safety of bosentan (dual blockade of endothelin receptors) has been demonstrated. In the first study (Study 351), bosentan was compared with placebo in 32 patients with pulmonary arterial hypertension (idiopathic or related to scleroderma) and an improvement in exercise capacity (sixminute walk test) and haemodynamics was observed for bosentan treatment after 12 weeks. The BREATHE- I (Bosentan Randomised trial of Endothelin Antagonist Therapy) trial produced comparable results in the same category ofpatients with pulmonary arterial hypertension. Patients were randomised to placebo (n=69) or to bosentan (62.5 mg, twice daily) followed four weeks later by 125 mg twice daily (n=74) or 250 mg twice daily (n=70) for 12 weeks. Again exercise capacity (six-minute walk test), NYHA functional class, Borg dyspnoea index and cardiac haemodynamics (in a subset of patients by Doppler echocardiography) improved with bosentan. Furthermore, the time to clinical worsening was extended in the bosentan group. In a subsequent open-label study, the patients from Study 351 were treated with bosentan for an additional year or were switched from placebo to bosentan. In both groups, the initial improvements in exercise capacity and NYHA class were maintained and a good safety profile was observed. In a retrospective study by Sitbon et al. (presented at the ATS meeting 2004), bosentan showed a better survival in
comparison with epoprostenol.
The third presentation, by M. Beghetti (Geneva, Switzerland) focussed on putting the evidence on congenital heart disease and pulmonary arterial hypertension into practice. In some forms of congenital heart disease, left-toright shunting occurs. Due to shear stress in the pulmonary arterioles, endothelial dysfunction develops 42
with proliferation ofsmooth muscle cells, increase in extracellular matrix and intravascular thrombosis. Therefore, pulmonary vascular resistance increases with a subsequent increase in pulmonary artery pressure. Finally, right ventricular pressure may become supra-systemic and the shunt inverts to a right-to-left shunt (Eisenmenger) with subsequent cyanosis. As a result of pulsatile stress and shear stress, endothelin secretion is increased. In congenital heart disease patients with increased pulmonary flow, increased levels of endothelin have been found. In an animal model of lambs with a leftto-right shunt, initial downregulation of ET-B receptor was observed followed by an increase in ET-A and ET-B receptors over time. In a piglet model of pulmonary arterial hypertension related to congenital heart disease, by Rondelet et al. treatment with dual blockade of the endothelin receptor prevented the increase in pulmonary vascular resistance. In clinical studies, preliminary results are encouraging as well. Firstly, in animal and human studies, a role for endothelin in the pathophysiology of lung dysfunction following cardiopulmonary bypass was suggested. In children undergoing cardiopulmonary bypass, increased levels ofendothelin have been found and in a lamb model increases in pulmonary vascular resistance were blocked by endothelin receptor blockade. In the BREATHE-3 study, the efficacy and safety of bosentan therapy in children was studied. Bosentan improved haemodynamic parameters of pulmonary arterial hypertension (idiopathic or related to congenital heart disease) after 12 weeks alone or in combination with epoprostenol. Pharmacokinetic profile, safety and tolerability of bosentan were similar in children to those of adults, obtained from other studies. During the ATS conference in 2004, pooled data from five European centres of 22 paediatric patients with pulmonary arterial hypertension (idiopathic or related
to congenital heart disease) were presented. Bosentan alone or in combination with epoprostenol or iloprost resulted in a stabilised or improved NYHA class in 85% of the patients, with a mean improvement of six-minute walk test of 30 metres (obtained in 16 patients). In a recent (non-randomised) study by Christensen et al. of nine patients with Eisenmenger syndrome started on bosentan 125 mg twice a day, six of the nine patients showed an improvement in NYHA class and mean 02 saturation increased. Only minor side effects and no changes in liver function were observed. Because of the limited data on the effect of bosentan in patients with pulmonary arterial hypertension due to congenital heart disease, the effect ofbosentan is currently being investigated in the BREATHE-5 study, in which patients with Eisenmenger's syndrome, randomised to bosentan or placebo, are compared in terms of systemic oxygen saturation, NYHA functional class, exercise capacity and Borg dyspnoea index.
The final presentation by N. Galie' (Bologna, Italy) focussed on the important role of cardiologists in pulmonary arterial hypertension management. Timely diagnosis of pulmonary arterial hypertension is essential because of the rapid progression of the disease when left untreated. However, symptoms of pulmonary arterial hypertension are non-specific and include dyspnoea on effort and fatigue, and late in the disease syncope and angina pectoris. Screening should be considered in patients with risk factors, such as the use of anorexantia, familial history of pulmonary arterial hypertension, connective tissue disease (scleroderma or SLEs), HIV infection and the presence of cardiac shunts or portal hypertension. As pulmonary arterial hypertension often occurs in patients with scleroderma, these patients should be followed annually with Doppler echocardiography. Differential diagnoses are seizures, coronary artery disease and heart
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failure. Physical examination, chest X-ray and electrocardiogram may point in a certain direction. However main diagnostic tool for identification ofpulmonary arterial hypertension is, transthoracic echocardiography. Mild pulmonary arterial hypertension is present when maximal velocity over the tricuspid annulus during diastole is 2.8 to 3.4 m/s (36 to 51 mmHg, when right atrial pressure is 5 mmHg). However, due to the inaccuracy of transthoracic echocardiography for exact measurement of pulmonary arterial pressures, right heart catherisation should be considered when Doppler echocardiographic estimation exceeds 40 to 45 mmHg, in the absence of intracardiac shunting. Furthermore, vasoreactivity should be tested during the same session. Definitive diagnosis is established when mean pulmonary artery pressure at rest exceeds 25 mmHg or 30 mmHg during exercise. In the classification of pulmonary hypertension, pulmonary function tests, arterial blood gas, CT scan, V/Q scan and lung scan can be helpful. Doppler echocardiography may also help in
the assessment of treatment effect by noninvasively measuring RV dilatation, LV size, stroke volume, cardiac index and LV diastolic filling characteristics. Treatment is considered when the patient is in NYHA class III. With a positive vasoreactivity test treatment with calcium channel blockers is effective in maximally 7 to 10% of patients. In non-responders, treatment with bosentan, prostanoid analogues (Iloprost, Beraprost) or epoprostenol can be started. The role of PDE 5 inhibitors (sildenafil) is currently limited. For patients in NYHA class IV, continuous intravenous administration of epoprostenol is proposed as a rescue therapy. Combination therapy can be attempted in selected cases. Balloon atrial septostomy and/or lung transplantation should be considered in the absence ofmedical treatment. In conclusion, this session handled the pathophysiological rationale for endothelin receptor blockade in
pulmonary arterial hypertension, the current data from clinical studies with bosentan, the initial
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results ofbosentan in patients with congenital heart disease, and the guidelines in the diagnosis and treatment of pulmonary arterial hypertension. During the discussion, the role of diuretics with bosentan was mentioned. In patients treated with bosentan and diuretics, fluid retention normally increases slightly and a slightly higher dose of diuretics should be given. The current role ofsildenafil is limited as only one, single-centre, non-randomised, not-blinded trial has been performed and no approval has been given yet for this drug in pulmonary arterial hypertension. Only when efficacy of current treatment options deteriorates and contraindications are absent should this treatment be considered. Finally, really longterm data are still lacking. It is not certain whether all patients with pulmonary arterial hypertension eventually progress and other treatment pathways should be investigated. However, fewer patients are being referred for lung transplantation. -