BOsentan for Mild Pulmonary Vascular Disease in Asd Patients (the BOMPA Trial): a Double-blind, Randomized Controlled, Pilot Trial

1. INTRODUCTION AND RATIONALE

1.1 MEDICAL BACKGROUND

Atrial septal defect (ASD) represents approximately 10% of all congenital heart diseases and is the third most common form of congenital heart defect. The incidence of congenital heart disease in Belgium is 1%, with ASD accounting for 25% of the cases (Data from the database of congenital heart diseases UZ Leuven.) Characterized by a free communication between the left and the right atrium, it may take the form of an ostium secundum defect (in the region of the fossa ovalis); an ostium primum defect (in the lower part of the atrial septum and associated with mitral regurgitation) or a sinus venosus defect (in the upper atrial septum and associated with anomalous drainage of one or more pulmonary veins)

Patients with atrial septal defect (ASD) initially present with a left-to-right shunt, which may cause elevated pulmonary artery pressures at rest and/or during exercise. However, this persistently elevated pulmonary blood-flow also causes progressive lesions of the pulmonary vasculature, as first described by Heath and Edwards. The earlier stages present with medial hypertrophy and/or intimal proliferation and are largely reversible after closure of the defect. Later stages, however, are irriversible: the origin of pulmonary arterial hypertension (PAH). Eventually, this volume and pressure overload of the right heart may lead to heart failure and/or arrhythmias. As PVR exceeds systemic resistance, the shunt is reversed (right-to-left shunt) leading to systemic arterial desaturation (and the related consequences: polyglobulia, hyperuricemia, decreased renal function and abnormal coagulation): the Eisenmenger syndrome (ES). When occlusive fibrotic lesions have developed later in life, closure of the ASD, although still feasible, may not result in complete normalization of pulmonary artery pressures. Moreover, it has been shown that closure after the age of 40 years is associated with worse outcome. It has been suggested that an abnormal increase in pulmonary artery pressures during exercise reflects mild pulmonary vascular disease. However, pulmonary artery pressures are defined by both cardiac output and pulmonary vascular resistance. During exercise, the relationship between pulmonary artery pressures and cardiac output is slightly curvilinear because of a natural distensibility of the pulmonary arterioles. Using bicycle stress echocardiography, pulmonary vascular resistance can be estimated either as a ratio of pulmonary artery pressure and cardiac output at each stage (total PVR) or by using linear regression analysis of the pressure-flow plots (dynamic PVR).

Prognosis of patients with unrepaired ASDs is thought to be shortened and repair can avoid right ventricular (RV) failure, pulmonary hypertension, thrombo-embolic events and atrial dysrrhythmias. So, when the defect is discovered early, an ASD is usually closed in childhood, unless the defect is considered not to be clinical significant. Sometimes, as most patients with an isolated ASD are asymptomatic during childhood, an ASD comes to medical attention at an older age.