A randomised, controlled trial of bosentan in severe COPD

Abstract

Pulmonary hypertension during exercise is common in severe chronic obstructive pulmonary disease (COPD). It was hypothesised that the use of the endothelin-receptor antagonist bosentan can improve cardiopulmonary haemodynamics during exercise, thus increasing exercise tolerance in patients with severe COPD.In the present double-blind, placebo-controlled study, 30 patients with severe or very severe COPD were randomly assigned in a 2:1 ratio to receive either bosentan or placebo for 12 weeks. The primary end-point was change in the 6-min walking distance. Secondary end-points included changes in health-related quality of life, lung function, cardiac haemodynamics, maximal oxygen uptake and pulmonary perfusion patterns.Compared with placebo, patients treated with bosentan during 12 weeks showed no significant improvement in exercise capacity as measured by the 6-min walking distance (mean¡SD 331¡123 versus 329¡94 m). There was no change in lung function, pulmonary arterial pressure, maximal oxygen uptake or regional pulmonary perfusion pattern. In contrast, arterial oxygen pressure dropped, the alveolar-arterial gradient increased and quality of life deteriorated significantly in patients assigned bosentan.The oral administration of the endothelin receptor antagonist bosentan not only failed to improve exercise capacity but also deteriorated hypoxaemia and functional status in severe chronic obstructive pulmonary disease patients without severe pulmonary hypertension at rest. KEYWORDS: Endothelin-receptor antagonist, exercise capacity, pulmonary hypertension, treatment P ulmonary hypertension (PH) at rest and during exercise is a very frequent complication in the natural history of chronic obstructive pulmonary disease (COPD) [1,2]. Correspondingly, this condition has been reported in 20-91% of patients with severe COPD and/or emphysema [3,4]. The presence of PH is commonly associated with more frequent use of healthcare resources and worse clinical outcome [5]. Remarkably, pulmonary artery pressure has been suggested to be the single best predictor of mortality in COPD [6].In COPD, PH is generally of moderate severity, but the range of mean pulmonary artery pressures varies substantially [7]. Moderate and severe PH are present in 9.8 and 3.7%, respectively, of the patients undergoing right heart catheterisation before lung volume reduction surgery [7]. Despite many uncertainties, studies indicate that 35% of all patients with severe COPD have pulmonary artery pressures of .20 mmHg at rest [8]. In addition, pulmonary pressures during exercise are greater than predicted by the pulmonary vascular resistance (PVR) equation in COPD, suggesting active pulmonary vasoconstriction on exertion [9]. Hence, of those patients without PH at rest, a further 52% are estimated to develop PH during exercise [5].There are many pathological similarities between idiopathic pulmonary arterial hypertension (PAH) and PH related to COPD. Like idiopathic PAH, pulmonary arteries in patients with COPD show evidence of fibromuscula...

Pulmonary hypertension in COPD: results from the ASPIRE registry

“…These observations support the hypothesis that hypoxia is not the sole driver of severe PH-COPD [2,33]. There is little data supporting the use of pulmonary vasodilators used in PAH in patients with PH-COPD [34][35][36][37]. However, there is growing interest in considering randomised controlled trials (RCTs) in this population, given the pulmonary haemodynamic characteristics of these patients.…”

Pulmonary Arterial Remodeling in Chronic Obstructive Pulmonary Disease is Lobe Dependent

“…3,4 Thus far, studies using selective and nonselective pulmonary vasodilators in COPD have not translated into improvements in meaningful clinical outcomes. [5][6][7][8][9][10][11] This has led to a renewed interest in the underlying pathogenesis of PH in COPD as a basis for determining the appropriateness of pursuing PH-specific therapies. 12 The pathogenesis of COPD-associated PH is complex.…”

Disproportionate Pulmonary Hypertension in a Patient with Early-onset Pulmonary Emphysema Treated with Specific Drugs for Pulmonary Arterial Hypertension

“…These findings have prompted clinicians to treat pulmonary hypertension in COPD with specific drugs for pulmonary arterial hypertension. Stolz et al reported that the endothelin receptor antagonist bosentan not only failed to improve exercise capacity but also deteriorated hypoxemia and functional status in severe COPD patients without severe pulmonary hypertension at rest (10). In a study of the phosphodiesterase-5 inhibitor sildenafil, Blanco et al concluded that sildenafil improved pulmonary hemodynamics at rest and during exercise in patients with COPD-associated pulmonary hypertension, while these effects were accompanied by impaired arterial oxygenation due to the inhibition of hypoxic vasoconstriction (11).…”

“…We would like to stress that specific drugs for pulmonary arterial hypertension may not be applicable to severe COPD patients with less severe pulmonary hypertension, because pulmonary vasodilators also have the potential to worsen gas exchange and oxygenation (10,11). These drugs should be used carefully in patients with severe pulmonary hypertension irrespective of the severity of COPD.…”