Endothelin-1 is a potent vasoconstrictor but also can promote fibrosis, cell proliferation and remodeling. Bosentan, an ETA and ETB receptor antagonist, has demonstrated potential benefits in animal models of pulmonary hypertension and pulmonary fibrosis (PF). The two pivotal clinical studies evaluating bosentan in patients with pulmonary arterial hypertension (PAH) included patients with idiopathic PAH and PAH related to connective tissue disease (CTD). However, the CTD patients with significant PF were excluded. The purpose of this pilot study was to evaluate the safety and potential benefit of bosentan in patients with PAH related to CTD with moderate to severe PF.
Patients with PAH related to CTD with significant underlying PF and WHO functional class III or IV were included in this study. PAH was suspected by echocardiography and confirmed by right heart catheterization. Bosentan, 62.5mg bid for 4 weeks followed by 125mg bid for 5 months, was added to the patient’s usual medication. Pulmonary function tests and echocardiography were done at baseline and after 6 months. Six minute walk test (6MWT) was done at baseline, 3 and 6 months. Laboratory assessments were carried out monthly.
During the 6 month period, all patients tolerated the treatment without significant elevation in liver transaminases levels or unexpected adverse events. WHO functional class was maintained (2 pts) or improved (3 pts). Over the 6 month period, the 6MWT distance mildly deteriorated in 2 patients and increased in 3 patients, resulting in a mean increase of 69.2 ± 127.4 meters.
The use of bosentan in patients with PAH related to CTD with moderate to severe PF appears safe and may induce a significant improvement in exercise tolerance. These findings should be further assessed in a larger cohort.
These patients should be considered for a trial treatment with bosentan in an attempt to improve their exercise tolerance, quality of life, and survival. Table 1:
Baseline DemographicsPt#AgeGenderDiagnosisVC (% pred)TLC (% pred)DLco (% pred)WHO ClassRVSP (mmHg)6MWT (m)133FScleroderma414119III55340268FMCTD534232III50260365FMCTD606236III95440460MScleroderma545219IV85240547MMCTD627225IV5020Mean ± SD54.6±14.554 ± 8.253.8 ± 13.226.2 ± 7.667 ± 21.4260 ± 155.5
VC=vital capacity; TLC=total lung capacity; DLco=diffusing capacity for carbon monoxide; RVSP=right ventricular systolic pressure; MCTD=mixed connective tissue disease
Z. Bshouty, None.