Longer-term bosentan therapy improves functional capacity in Eisenmenger syndrome: Results of the BREATHE-5 open-label extension study

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Abstract

Background

Bosentan, an oral endothelin ETA/ETB receptor antagonist, improves hemodynamics and exercise capacity in patients with Eisenmenger syndrome but longer-term effects are unknown. This study investigated the efficacy and safety of bosentan up to 40 weeks in these patients.

Methods

Following the 16-week, double blind, placebo-controlled BREATHE-5 study of bosentan in patients with Eisenmenger syndrome, an open-label extension (OLE) was performed. Patients who completed BREATHE-5 received bosentan for an additional 24 weeks (62.5 mg b.i.d. for 4 weeks, then 125 mg b.i.d.) and were analyzed in two groups; ex-placebo and ex-bosentan, according to BREATHE-5 treatment.

Results

Thirty-seven patients with Eisenmenger syndrome who participated in BREATHE-5 were included in the OLE. At week 24, the 6-minute walk distance (mean ± SE) increased from OLE baseline for the ex-placebo (+ 33.2 ± 23.9 m) and ex-bosentan group (+ 6.7 ± 10.0 m). The overall improvement from baseline of BREATHE-5 was + 61.3 ± 8.1 m (95% confidence interval: [44.7, 78.0]) for the ex-bosentan group. WHO functional class was improved in both groups. Bosentan did not reduce systemic arterial blood oxygen saturation; safety profile was comparable to previous trials.

Conclusions

In conclusion, these longer follow-up data support the efficacy and safety profile reported in the preceding BREATHE-5 study of bosentan treatment of Eisenmenger syndrome, challenging the notion that pulmonary vascular disease and severe functional impairment in these patients are not amenable to therapy.

Introduction

The first placebo-controlled study in Eisenmenger syndrome (ES), BREATHE-5, demonstrated that bosentan significantly improved 6-minute walk distance (6MWD) and reduced pulmonary vascular resistance index (PVRi), without compromising oxygen saturation (SpO2) [1]. However, longer-term efficacy and safety data are still lacking for patients with pulmonary arterial hypertension (PAH) in the context of ES.

Eisenmenger syndrome is the most advanced form of PAH in association with congenital heart disease (CHD). A large non-restrictive intra- or extra-cardiac communication leads with time to reversal of the left to right shunt and subsequent cyanosis. Most ES patients survive into adulthood, and have a reported 3-year survival rate of 77%, compared with just 35% for untreated idiopathic PAH (iPAH) patients [2]. Nevertheless, ES has a significant impact on both morbidity and mortality [3], [4]. ES patients have additional morbidities that are atypical of iPAH patients, including haemoptysis, cerebrovascular incidents, brain abscesses, secondary erythrocytosis and coagulation abnormalities [5]. Survival depends largely on right ventricular function, which is initially preserved in ES patients due to the “training effect” secondary to long-standing right ventricular hypertension, but worsens over time. Consequently, as the disease progresses, the functional status of the patient deteriorates, and despite living longer, as a group, ES patients have the worst functional capacity of all CHD patients [2].

Conventional therapy addresses symptomatic patients, and is directed at avoiding or managing complications [6], but this approach has not led to significant improvement of functional capacity or long-term outcome for decades [7], [8]. Bosentan, an oral dual (ETA/ETB) endothelin receptor antagonist, improves functional capacity and has the potential to reverse cardiopulmonary hemodynamics [9], and thereby may improve patients' long-term outcome prospects.

The present study is an open-label extension (OLE) to the double blind, placebo-controlled BREATHE-5 study. It was designed to assess the efficacy and safety of bosentan up to 40 weeks for the treatment of patients with ES.

Section snippets

Patients

Enrolled patients with PAH related to ES, had completed the BREATHE-5 trial, and had elected to enter the BREATHE-5 OLE study. PAH was confirmed prior to enrolment in the BREATHE-5 study by cardiac catheterization, and defect size was determined echocardiographically. Stable PAH upon completion of the BREATHE-5 trial was required. Phosphodiesterase inhibitors, prostanoids and investigational endothelin receptor antagonists were not allowed during the study. To avoid potential drug interactions,

Results

Thirty-seven patients completing the double blind placebo-controlled BREATHE-5 study were included in the OLE; 11 patients had been randomized to placebo in the previous study and 26 to bosentan.

Discussion

The BREATHE-5 trial and the present OLE challenge the notion that pulmonary vascular disease amongst patients with ES [12] is not amenable to therapy. In the double blind placebo-controlled BREATHE-5 study in patients with PAH related to ES (WHO FC III) [1], bosentan led to significant improvements in hemodynamics (− 472.0 ± 221.9 dyn s cm 5 for PVRi) and exercise capacity (+ 53.1 ± 19.2 m for 6MWD). The observed improvements in exercise capacity were maintained in the ex-bosentan group for up to

Conflict of interest disclosures

Michael A. Gatzoulis, MD, PhD has served on the advisory boards of Pfizer and Actelion and has received lecture fees and grant support from Actelion.

Maurice Beghetti, MD, has served on the advisory boards of Actelion, INO therapeutics and Mondobiotech and has received lecture fees from Actelion, INO therapeutics and Schering and grant support from Actelion and Schering.

Nazzareno Galiè, MD, has served on the advisory boards of Pfizer, Actelion, Schering, Encysive, Myogen, and Mondobiotech and

Acknowledgements

This study was supported by Actelion Pharmaceuticals Ltd. Allschwil, Switzerland.

The authors would like to acknowledge the collaboration and commitment of all the local investigators and their staff: Germany: John Hess, MD, Deutsches Herzzentrum München, München. Italy: Alessandra Manes, MD, University of Bologna, Bologna. Mario Vigano, MD, San Matteo Hospital, Pavia; Netherlands: Elke S. Hoendermis, MD, University Medical Center of Groningen, Groningen. Spain: José Maria Oliver, MD, Hospital

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