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