Elsevier

The Lancet

Volume 358, Issue 9288, 6 October 2001, Pages 1119-1123
The Lancet

Articles
Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebocontrolled study

https://doi.org/10.1016/S0140-6736(01)06250-XGet rights and content

Summary

Background

Endothelin 1, a powerful endogenous vasoconstrictor and mitogen, might be a cause of pulmonary hypertension. We describe the efficacy and safety of bosentan, a dual endothelin-receptor antagonist that can be taken orally, in patients with severe pulmonary hypertension.

Methods

In this double-blind, placebo-controlled study, 32 patients with pulmonary hypertension (primary or associated with scleroderma) were randomly assigned to bosentan (62:5 mg taken twice daily for 4 weeks then 125 mg twice daily) or placebo for a minimum of 12 weeks. The primary endpoint was change in exercise capacity. Secondary endpoints included changes in cardiopulmonary haemodynamics, Borg dyspnoea index, WHO functional class, and withdrawal due to clinical worsening. Analysis was by intention to treat.

Findings

In patients given bosentan, the distance walked in 6 min improved by 70 m at 12 weeks compared with baseline, whereas it worsened by 6 m in those on placebo (difference 76 m [95% CI 12-139], p=0<021). The improvement was maintained for at least 20 weeks. The cardiac index was 1·0 L min−1 m−2 (95% CI 0·6-1·4, p<0·0001) greater in patients given bosentan than in those given placebo. Pulmonary vascular resistance decreased by 223 dyn s cm−5 with bosentan, but increased by 191 dyn s cm−5 with placebo (difference -415 [-608 to -221], p=0·0002). Patients given bosentan had a reduced Borg dyspnoea index and an improved WHO functional class. All three withdrawals from clinical worsening were in the placebo group (p=0·033). The number and nature of adverse events did not differ between the two groups.

Interpretation

Bosentan increases exercise capacity and improves haemodynamics in patients with pulmonary hypertension, suggesting that endothelin has an important role in pulmonary hypertension.

Introduction

Primary pulmonary hypertension is a disease resulting in progressive deterioration that is characterised by an increase in pulmonary vascular resistance leading to right ventricular failure and death.1 Pulmonary hypertension can arise in isolation (primary pulmonary hypertension), or as a complication of systemic diseases (eg, systemic sclerosis or scleroderma).2 Conventional therapy with vasodilators3, 4 and anticoagulants3 is effective for only a few patients. The US National Institutes of Health (NIH) registry of patients with primary pulmonary hypertension records a median life expectancy of 2·8 years from diagnosis.5 Similarly, patients with pulmonary hypertension associated with scleroderma have a survival of 40-55% at 2 years.2 Epoprostenol has been shown to be more effective than conventional treatment and has greatly improved the life expectancy of patients with severe pulmonary hypertension.6 However, epoprostenol requires permanent intravenous access and is associated with many side-effects and complications.6, 7 The success of long-term intravenous epoprostenol prompted development of analogue molecules that can be inhaled (eg, iloprost8). or taken orally (eg, beraprost9). However, no randomised, placebo-controlled trials have been done with these new treatments.

That endothelin 1 has a pathogenic role in pulmonary hypertension has been documented.10 It is both a potent vasoconstrictor and a smooth-muscle mitogen, and might therefore contribute to the increase in vascular tone and the pulmonary vascular hypertrophy associated with pulmonary hypertension. Patients with primary pulmonary hypertension11 or diffuse scleroderma12 have high concentrations of endothelin 1 in plasma, which are inversely correlated with outlook.11 High concentrations of endothelin 1 have also been recorded in the lungs of patients with pulmonary hypertension,13 idiopathic pulmonary fibrosis,14 or postobstructive pulmonary vasculopathy,15 suggesting that new treatments for pulmonary hypertension could act by blocking endothelin receptors.

Bosentan (Ro 47-0203), an orally active non-peptide antagonist of both endothelin receptor subtypes (ETA and ETB), has been shown to decrease inflammatory reactions, prevent increase in permeability of pulmonary vessels, and prevent development of fibrosis in animals with pulmonary inflammation.16, 17 In rats with chronic pulmonary hypertension, bosentan reduces pulmonary arterial pressure, pulmonary vascular hypertrophy, and right ventricular hypertrophy, without inducing systemic vasodilatation.18 In a pilot study19 of acute administration of high doses of bosentan to patients with pulmonary hypertension, pulmonary and systemic resistance decreased, suggesting that chronic doses might be necessary for a significant and selective effect. Thus, the clinical effects of bosentan as a long-term oral treatment still need to be assessed. We assessed the effects of bosentan on exercise capacity and cardiopulmonary haemodynamics, and the safety and tolerability of bosentan in patients with pulmonary arterial hypertension.

Section snippets

Methods Patients

We recruited patients who had symptomatic, severe, primary pulmonary hypertension or pulmonary hypertension due to scleroderma (in functional classes III-IV according to 1998 WHO classification20), despite previous treatment with vasodilators, anticoagulants, diuretics, cardiac glycosides, or supplemental oxygen. Patients were included if they had a baseline 6-min walking distance of between 150 m and 500 m, a mean pulmonary artery pressure of greater than 25 mm Hg, a pulmonary capillary wedge

Procedures

The study was a double-blind, randomised, placebocontrolled trial that was done in five centres in the USA and one in France. 32 patients were randomly assigned 62·5 mg bosentan twice daily for the first 4 weeks followed by the target dose (125 mg twice daily) unless drugrelated adverse events arose (eg, hypotension), or matching doses of placebo. Randomisation was computer generated using the Almedica Drug Labelling System, with a block size of three. The 2/1 randomisation ratio

Statistical analysis

A sample size of 30 patients was calculated to detect a mean difference of 50 m (SD 50) in the 6-min walk test from baseline to week 12, with 80% power, and at a onesided α level of 0·05 by Student's t test. To keep bias to a minimum, missing data at the week-12 assessment were derived from predefined replacement rules. Discontinuation of study medication because of clinical worsening was analysed with the patient's assessment at the time of premature withdrawal (in patients who died or had

Results

Of 36 patients recruited, 32 were included in the study; 21 were assigned to bosentan and 11 placebo (figure 1). We excluded four patients because they did not meet all the entry criteria. All patients remained in the study until the last patient had completed the week 12 assessments, unless they were withdrawn because of clinical worsening. As a result, the total length of treatment varied from 83 to 202 days. No code break took place before the week 12 assessment.

Treatment groups were well

Discussion

Our results show that chronic oral administration of a dual endothelin-receptor antagonist significantly improved exercise capacity and cardiopulmonary haemodynamics in patients with primary pulmonary hypertension or pulmonary hypertension due to scleroderma. Moreover, bosentan consistently improved all endpoints studied. Exercise capacity and haemodynamic function either deteriorated or remained unchanged in patients given placebo, as would be expected from clinical experience. The effect of

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