Atrial septal defects versus ventricular septal defects in BREATHE-5, a placebo-controlled study of pulmonary arterial hypertension related to Eisenmenger's syndrome: A subgroup analysis

doi:10.1016/j.ijcard.2009.04.037

International Journal of Cardiology

Volume 144, Issue 3, 29 October 2010, Pages 373-378

https://doi.org/10.1016/j.ijcard.2009.04.037 Get rights and content

Abstract

Background

Eisenmenger's syndrome (ES) is the most advanced form of pulmonary arterial hypertension related to congenital heart disease. Evolution of pulmonary vascular disease differs markedly between patients with atrial septal defects (ASD) versus ventricular septal defects (VSD), potentially affecting response to treatment. We compared the effects of bosentan and placebo in patients with isolated ASD (ASD subgroup) versus patients with isolated VSD or both defects (VSD subgroup).

Methods

Post-hoc analysis of a 16-week, multicenter, randomized, double-blind, placebo-controlled trial was performed. Fifty-four patients (13: ASDs, 36: VSDs, 5: VSD + ASD) were randomized to bosentan 62.5 mg bid for four weeks (uptitrated to 125 mg bid thereafter) or placebo. Main outcome measures were: indexed pulmonary vascular resistance (PVRi), exercise capacity, mean pulmonary artery pressure (mPAP), pulmonary blood flow index (Qpi), and changes in oxygen saturation (SpO₂).

Results

Placebo-corrected median (95% CI) treatment effects on PVRi were − 544.0 dyn·s·cm^− 5 (− 1593.8, 344.7) and − 436.4 dyn·s·cm^− 5 (− 960.0, 167.0) in the ASD and VSD subgroups, respectively. Effects of bosentan on exercise capacity and mPAP were similar in both subgroups. No changes in SpO₂ or Qpi were observed in either bosentan or placebo subgroups.

Conclusions

Improvements in exercise capacity and cardiopulmonary hemodynamics, without desaturation, were observed in ES patients with both ASDs and VSDs. Although not reaching statistical significance, improvements were similar to those in the BREATHE-5 analyses, suggesting that the location of septal defects is not a key determinant of treatment response. These data further support the use of bosentan for the treatment of ES, independent of shunt location.

Introduction

The occurrence of pulmonary arterial hypertension related to congenital heart disease (PAH–CHD) is common and well documented, particularly among patients with septal defects [1], [2]. Such patients may initially exhibit a ‘left-to-right’ (systemic-to-pulmonary) shunt via their congenital defect. Increased blood flow exposes the pulmonary vasculature to disproportionate levels of shear stress and circumferential stretching, leading to vascular remodeling and elevated pulmonary vascular resistance [3], [4]. Increasing pulmonary vascular resistance influences shunt direction, initially causing bi-directional circulatory flow through the defect, which eventually undergoes a complete reversal to a right-to-left (pulmonary-to-systemic) shunt, associated with cyanosis and reduced exercise capacity [1]. This hemodynamic physiology classically defines Eisenmenger's syndrome (ES), the most severe form of PAH–CHD [5], [6], [7], [8].

Eisenmenger's syndrome frequently occurs in patients with large, non-restrictive intra- or extra-cardiac communications, including ventricular septal defects (VSD), atrial septal defects (ASD), and patent ductus arteriosus [2], [9], [10]. The likelihood of patients with CHD developing ES is dependent on the underlying cardiac defect [11], [12], [13]. Several studies have suggested that the location of the septal defect causes differences in natural course and circulatory physiology between patients with ES [2], [9], [12]. These reports posit that such differences may be explained by adaptive mechanisms resulting from the varying loading conditions intrinsic to particular anatomic variations in ES patients. The presence of a septal defect in PAH is presumed to be beneficial because of the potential for unloading of the right ventricle and maintenance of cardiac output, albeit at the cost of cyanosis. It has been hypothesized that these beneficial effects differ between patients with isolated pre-tricuspid shunts compared to those with post-tricuspid shunts. In ES patients with ASDs, this unloading occurs only late in the disease course when the right atrium and ventricle start to fail. By contrast, in patients with large non-restrictive VSDs for whom systolic shunting begins earlier in the course of ES, this unloading is hypothesized to occur early. In patients with large post-tricuspid lesions, shunting is considered to be directly dependent on the ratio between pulmonary vascular resistance index and systemic vascular resistance index (PVRi/SVRi), rather than right atrial–ventricular failure and subsequent elevation of filling pressures. Patients with large post-tricuspid lesions — with or without atrial septal defects — may therefore be at greater risk of clinical deterioration due to the decreased SVR induced by vasodilator treatment. Therefore, in this study, we categorized all patients with post-tricuspid lesions into a single subgroup for analysis.

The BREATHE-5 study was the first multicenter, randomized, double-blind, placebo-controlled study to investigate the oral dual endothelin receptor antagonist bosentan in patients with ES, including patients with pre-tricuspid (ASDs) and post-tricuspid (VSDs) lesions [14]. In the total study population, treatment using bosentan increased exercise capacity and improved hemodynamics [14]. To examine the concept that bosentan treatment-effect is dependent on anatomy and physiology of intracardiac/vascular shunting in patients with ES, we retrospectively compared outcomes between patients with ASDs and VSDs treated during the initial BREATHE-5 study either with bosentan or placebo.

Section snippets

Study design

The design of the multicenter, randomized, double-blind, placebo-controlled BREATHE-5 study of bosentan (62.5 mg BID, increasing to 125 mg BID after 4 weeks for a further 12 weeks) in patients with ES has been reported previously [14]. The study (NCT00367770) was conducted according to the most recent amendments to the Declaration of Helsinki and in adherence to good clinical practice guidelines. Local institutional review boards or independent ethics committees approved the protocol, and

Patient demographics

The BREATHE-5 study included a total of 54 patients; 13 patients exhibited an ASD (24.1%), 36 patients exhibited a VSD (66.7%) and five patients exhibited a VSD in combination with an ASD (9.3%). Baseline patient characteristics for each of the subgroups are summarized in Table 1. Patients with an ASD appeared to be older and to have lower PVRi and mPAP in comparison to patients in the VSD subgroup within each treatment group. Details of previous or concomitant medications at baseline are also

Discussion

In this post hoc subgroup analysis of the BREATHE-5 study, patients in both the ASD and the VSD subgroups experienced improvements in cardiopulmonary hemodynamics following bosentan treatment, with no unexpected adverse events.

In common with other vasodilatory agents, there was a theoretical risk that bosentan might aggravate the right-to-left cardiac shunt in ES patients due to decreases in systemic vascular resistance, resulting in worsening cyanosis and exercise capacity. This risk is

Acknowledgements

We acknowledge the collaboration and commitment of all the local investigators and their staff: Australia: David Celermajer, MD, Central Clinical School, Camperdown; Leeanne Grigg, Royal Melbourne Hospital, Parkville. Austria: Helmut Baumgartner, MD, Universitätsklinik für Innere Medizin, Vienna. Belgium: Luc Mertens, MD, UZ Gasthuisberg, Leuven. Canada: Michael Connelly, MD, Peter Lougheed Centre, Calgary; Rima Hosn, MD, Toronto General Hospital, Toronto. Germany: John Hess, MD, Deutsches

References (21)

E.B. Berman et al.
Eisenmenger's syndrome: current management
Prog Cardiovasc Dis
(2002)
K. Niwa et al.
Eisenmenger syndrome in adults: ventricular septal defect, truncus arteriosus, univentricular heart
J Am Coll Cardiol
(1999)
W.J. Cantor et al.
Determinants of survival and length of survival in adults with Eisenmenger syndrome
Am J Cardiol
(1999)
R.N. Channick et al.
Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study
Lancet
(2001)
A.J. Coats
Ethical authorship and publishing
Int J Cardiol
(2009)
W. Vongpatanasin et al.
The Eisenmenger syndrome in adults
Ann Intern Med
(1998)
G.P. Diller et al.
Pulmonary vascular disease in adults with congenital heart disease
Circulation
(2007)
J.I. Hoffman et al.
Pulmonary vascular disease with congenital heart lesions: pathologic features and causes
Circulation
(1981)
M. Rabinovitch
It all begins with EVE (endogenous vascular elastase)
Isr J Med Sci
(1996)
P. Wood
The Eisenmenger syndrome or pulmonary hypertension with reversed central shunt
Br Med J
(1958)

There are more references available in the full text version of this article.

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Eisenmenger syndrome is the most severe and extreme phenotype of pulmonary arterial hypertension associated with congenital heart disease. A large nonrestrictive systemic left-to-right shunt triggers the development of pulmonary vascular disease, progressive pulmonary arterial hypertension, and increasing pulmonary vascular resistance at the systemic level, which ultimately results in shunt reversal. Herein, we review the changing epidemiological patterns and pathophysiology of Eisenmenger syndrome. Multiorgan disease is an integral manifestation of Eisenmenger syndrome and includes involvement of the cardiac, hematological, neurological, respiratory, gastrointestinal, urinary, immunological, musculoskeletal, and endocrinological systems. Standardized practical guidelines for the assessment, management, risk stratification, and follow-up of this very fragile and vulnerable population are discussed. Multidisciplinary care is the best clinical practice. An approach to the prevention and management of a broad spectrum of complications is provided. Relevant therapeutic questions are discussed, including anticoagulation, noncardiac surgery, physical activity, transplantation, and advanced-care planning (palliative care). Advanced pulmonary arterial hypertension therapies are indicated in patients with Eisenmenger syndrome and World Health Organization functional class II or higher symptoms to improve functional capacity, quality of life, and—less well documented—survival. Specific recommendations regarding monotherapy or combination therapy are provided according to functional class and clinical response. The ultimate challenge for all care providers remains early detection and management of intracardiac and extracardiac shunts, considering that Eisenmenger syndrome is a preventable condition.
Le syndrome d'Eisenmenger est le phénotype le plus sévère et extrême de l'hypertension artérielle pulmonaire associée aux cardiopathies congénitales. Un important shunt gauche-droit systémique non restrictif engendre une maladie vasculaire pulmonaire, l'apparition d'une hypertension artérielle pulmonaire et la majoration des résistances vasculaires pulmonaires; les pressions pulmonaires atteignent un seuil systémique à l'origine du renversement du shunt. Cet article discute des bases physiopathologiques et du changement épidémiologique du syndrome d'Eisenmenger. L'atteinte multiviscérale est caractéristique du syndrome d'Eisenmenger impliquant le système cardio-vasculaire, hématologique, neurologique, respiratoire, gastro-intestinal, urinaire, immunologique, musculo-squelettique et endocrinien. Nous proposons des lignes directrices pratiques pour l’évaluation, la prise en charge, la stratification des risques et le suivi de cette population fragile et vulnérable. Les pratiques cliniques exemplaires recommandent des soins multidisciplinaires. Nous présentons aussi une approche pour la prévention et la prise en charge d'un grand éventail de complications et nous abordons des questions thérapeutiques pertinentes, notamment l'anticoagulothérapie, la chirurgie non cardiaque, l'activité physique, la greffe et la planification préalable des soins (soins palliatifs). Les traitements spécifiques de l'hypertension artérielle pulmonaire sont indiqués chez les patients atteints de syndrome d'Eisenmenger avec une classe fonctionnelle de II ou plus de l'Organisation mondiale de la Santé afin d'améliorer la capacité fonctionnelle, la qualité de vie, et bien que moins documentée la survie. Enfin, nous formulons des recommandations spécifiques concernant le recours à la monothérapie ou à l'association thérapeutique selon la classe fonctionnelle et la réponse clinique. Le diagnostic précoce et la prise en charge optimale des shunts intracardiaques et extracardiaques sont les défis ultimes des équipes traitantes médicales pour prévenir le syndrome d'Eisenmenger.
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La hipertensión arterial pulmonar se encuentra comúnmente en adultos con cardiopatías congénitas. De acuerdo con el tipo de defecto, el momento de la corrección y la repercusión hemodinámica será la magnitud del compromiso y a su vez, un determinante esencial en la posibilidad de realizar manejo correctivo en aquellos pacientes diagnosticados de manera tardía. Se hizo una revisión de la información disponible en cuanto a la clasificación, el diagnóstico y el manejo de acuerdo con la posibilidad de intervención, el tratamiento general y el uso de vasodilatadores pulmonares, con énfasis en las recomendaciones especiales para el manejo de los pacientes con síndrome de Eisenmenger.
Pulmonary arterial hypertension is commonly found in adults with congenital heart diseases. The magnitude of the compromise will depend on the type of defect, the time of the correction, and the haemodynamic repercussion, and, in turn will be an essential determining factor in the possibility of performing corrective management in those patients with delayed diagnoses. A review is presented on the information available as regards the classification, diagnosis, and management depending on the possibility of intervention, the general treatment, and use of pulmonary vasodilators, with an emphasis on the special recommendations for the management of patients with Eisenmenger syndrome.
Long-term outcomes of pulmonary arterial hypertension under specific drug therapy in Eisenmenger syndrome
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Citation Excerpt :
In our cohort, post-tricuspid defects were associated with worse hemodynamic parameter values.28,29 Overall, hemodynamic changes induced by PAH-SDT were not significantly different between these 2 groups, in keeping with a sub-group analysis of data from BREATHE-5.29 However, in the patient-by-patient analysis, the hemodynamic improvement pattern was noted in only approximately 43% of the patients with post-tricuspid defects compared with approximately 78% of patients with pre-tricuspid defects.
The long-term effectiveness of pulmonary arterial hypertension–specific drug therapy (PAH-SDT) in Eisenmenger syndrome is controversial. We investigated short-term and long-term hemodynamic changes under PAH-SDT and their associations with outcomes in a bicentric cohort.
Over 20 years, we included 69 patients with congenital heart disease, an indexed pulmonary vascular resistance (PVRi) >8 WU·m², and 292 standardized catheterizations at baseline and after PAH-SDT initiation or intensification. Oxygen consumption was measured and the Fick principle applied to calculate indexed pulmonary output (Qpi) and PVRi.
After PAH-SDT initiation or intensification, median (interquartile range) PVRi decrease was 5.1 WU·m² (−1.4, −12.6) (p < 0.0001). Median Qpi and 6-minute walk test increases were +0.4 liter/min/m² (0.0, +0.9) (p < 0.0001) and +49 m (+15, +93) (p = 0.0003), respectively. Hemodynamic response combining increased Qpi with decreases in transpulmonary gradient and PVRi occurred in 68.0% of patients. After a median of 4.9 years, PVRi and Qpi changes were no longer significant. Over a median of 7.2 years, 23 (33.3%) patients met a composite criterion (death, n = 8; heart-lung transplantation or listing for transplantation, n = 15). The 15-year cumulative event rate was 49.2%. By multivariate analysis, independent predictors of events were superior vena cava oxygen saturation and hemodynamic response (p = 0.048 and p < 0.0001).
In Eisenmenger syndrome, PAH-SDT induces early hemodynamic improvements, which decline over time. Hemodynamic changes under PAH-SDT vary across patients. Hemodynamic parameters at baseline and under PAH-SDT are associated with events. PAH-SDT may need to be individualized based on hemodynamic changes.
Heart Failure, Exercise Intolerance, and Physical Training
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Physiological differences between various types of Eisenmenger syndrome and relation to outcome
2015, International Journal of Cardiology
Eisenmenger syndrome (ES) is the most advanced form of pulmonary arterial hypertension (PAH) related to congenital heart disease. Several studies have suggested that the presence and location of the shunt defines the natural history of these patients by influencing right ventricular adaptation to PAH. We aimed to echocardiographically assess differences in cardiac physiology and outcome between various types of ES.
In this longitudinal cohort study, 191 patients with ES and non-complex congenital heart disease were recruited, 36 with pre-tricuspid and 155 with post-tricuspid shunts. Patients with pre-tricuspid shunts were older, had higher BNP concentrations and lower exercise tolerance compared to patients with post-tricuspid shunts. Right ventricular (RV) function was impaired in patients with atrial septal defects, with larger right ventricles, impaired systolic function and adaptation. The left ventricular eccentricity index was significantly higher in pre-tricuspid defects. Within post-tricuspid shunts, patients with atrio-ventricular septal defects had better right ventricular function compared to ventricular septal defects, while in those with a patent ductus arteriosus this was worse. There was a trend towards lower mortality in patients with post versus pre-tricuspid shunts, which was significant for patients above the age of 48 years.
The presence of a post-tricuspid shunt appears to carry physiological and possibly prognostic benefits in ES compared to patients with pre-tricuspid shunts. This should be borne in mind when management decisions and advanced therapies are considered.

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^☆: Grant support: This study was supported by Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.

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Atrial septal defects versus ventricular septal defects in BREATHE-5, a placebo-controlled study of pulmonary arterial hypertension related to Eisenmenger's syndrome: A subgroup analysis☆

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Study design

Patient demographics

Discussion

Acknowledgements

Prog Cardiovasc Dis

J Am Coll Cardiol

Am J Cardiol

Lancet

Int J Cardiol

The Eisenmenger syndrome in adults

Ann Intern Med

Pulmonary vascular disease in adults with congenital heart disease

Circulation

Pulmonary vascular disease with congenital heart lesions: pathologic features and causes

Circulation

It all begins with EVE (endogenous vascular elastase)

Isr J Med Sci

The Eisenmenger syndrome or pulmonary hypertension with reversed central shunt

Br Med J