Chronic thromboembolic pulmonary hypertension (CTEPH) is a devastating disease in which the pulmonary vasculature becomes obstructed by organised fibrotic material, presumed to be the consequence of incomplete resolution of pulmonary emboli. The ensuing increased pulmonary vascular resistance and right ventricular dysfunction results in severe exercise limitation, symptomatic right heart failure, and markedly impaired survival.

Recent studies suggest that the frequency of this condition is higher than previously appreciated, occurring in up 3.8% of patients following acute pulmonary embolism after 2 years.¹ The treatment of choice is pulmonary endarterectomy (PEA), a potentially curative surgical procedure in which the fibrotic material is removed from the proximal pulmonary arteries during periods of circulatory arrest.²

However, in response to increased flow and shear stress through vascular segments unobstructed by proximal thrombotic material, some individuals also develop a small vessel arteriopathy. This so called “distal CTEPH” has a pathophysiology not dissimilar to that of idiopathic pulmonary arterial hypertension.³ In such patients, PEA may be unsuccessful in alleviating the pulmonary hypertension, and at the present time there is no licensed medical treatment for this condition.

As the national referral centre for PEA for the UK, we sought to assess the efficacy of the oral endothelin receptor antagonist bosentan in patients with distal CTEPH. This agent has established efficacy in pulmonary arterial hypertension, and in distal CTEPH endothelin-1 is thought to play an equally important role in the progressive nature of pulmonary vascular remodelling.⁴

Twenty patients with established distal CTEPH were recruited to the study, 15 deemed inoperable because of the distribution of their disease on imaging and five with persisting pulmonary hypertension following PEA. All subjects received open label bosentan 125 mg twice daily for at least 3 months. Assessments of change in 6 minute walk distance (6MWD), modified New York Heart Association Classification (NYHA), and haemodynamics were made. After at least 3 months of treatment there were significant improvements in 6MWD, NYHA classification, cardiac index, total pulmonary resistance, and pulmonary vascular resistance (table 1). All patients were alive at 3 months and no significant adverse events were reported as a result of the treatment. In particular, hepatic transaminases, which were monitored on a monthly basis, remained within the acceptable range in all participants.

Although uncontrolled, these preliminary data suggest that treatment with bosentan in this otherwise progressive condition results in improvement in exercise capacity, function, and haemodynamic prognostic markers. It is likely that, by inhibiting the action of endothelin-1, bosentan reduces the abnormal endothelial and smooth muscle cell proliferation stimulated by high shear stress within non-occluded pulmonary arterioles. This gradual reversal of vascular remodelling is the most likely reason for the reduction in pulmonary vascular resistance and right ventricular afterload and improved cardiac output observed in our subjects.

Pulmonary endartectomy remains the treatment of choice for proximal CTEPH. However, in patients with established distal arteriopathy deemed unsuitable for this surgical intervention, bosentan may offer an option by which to delay the progression of this otherwise devastating disease.