Activation of the endothelin system has been demonstrated in both plasma and lung tissue of PAH ( pulmonary arterial hypertension ) patients. Although it is unclear if the increases in endothelin-1 plasma levels are a cause or a consequence of pulmonary hypertension, these data support a prominent role for the endothelin system in the pathogenesis of pulmonary arterial hypertension.
Endothelin-1 exerts vasoconstrictor and mitogenic effects by binding to two distinct receptor isoforms in the pulmonary vascular smooth muscle cells, endothelin receptors type A and B.
Ambrisentan is an ERA that preferentially binds with endothelin receptor type A. Ambrisentan has been evaluated in a pilot study and in two large RCTs that have demonstrated efficacy on symptoms, exercise capacity, haemodynamics and time to clinical worsening of patients with IPAH and PAH associated with CTD and HIV infection.
The incidence of abnormal liver function tests ranges from 0.8 to 3%. Monthly liver function assessment is not mandated in the USA.
An increased incidence of peripheral oedema has been reported with Ambrisentan use.
Bosentan is an oral active dual endothelin receptor type A and B antagonist and the first molecule of its class to be synthesized. Bosentan has been evaluated in PAH ( idiopathic, associated with CTD and Eisenmenger syndrome ) in six RCTs ( Study-351, BREATHE-1, BREATHE-2, BREATHE-5, EARLY and COMPASS 2 ), which showed improvement in exercise capacity, FC, haemodynamics, echocardiographic and Doppler variables and time to clinical worsening.
Increases in hepatic aminotransferases occurred in approximately 10% of the patients and were found to be dose dependent and reversible after dose reduction or discontinuation. For these reasons, liver function testing should be performed monthly in patients receiving Bosentan.
The dual ERA Macitentan has been evaluated in an event-driven RCT: 742 PAH patients were treated with 3 mg or 10 mg Macitentan as compared with placebo for an average of 100 weeks. The primary endpoint was the time from the initiation of treatment to the first occurrence of a composite endpoint of death, atrial septostomy, lung transplantation, initiation of treatment with i.v. or subcutaneous prostanoids or worsening of pulmonary arterial hypertension. Macitentan significantly reduced this composite endpoint of morbidity and mortality among patients with pulmonary arterial hypertension and also increased exercise capacity. Benefits were shown both for patients who had not received treatment previously and for those receiving additional therapy for pulmonary arterial hypertension.
While no liver toxicity was shown, reduction in blood haemoglobin less than or equal to 8 g/dl was observed in 4.3% of patients receiving 10 mg of Macitentan. ( Xagena )
Source: European Society of Cardiology, 2015 [ 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension ]