Prolonged beneficial effect of bosentan treatment and 4-year survival rates in adult patients with pulmonary arterial hypertension associated with congenital heart disease

Abstract

Pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD) due to systemic to pulmonary shunting is associated with a high risk of morbidity and mortality. In this study we evaluated 4 years treatment effect of bosentan on exercise capacity and quality of life and survival rates in 64 adult patients with PAH associated with CHD, including patients with Down syndrome (DS). All patients were evaluated at baseline and during follow-up with laboratory tests, 6-minute walk test, quality of life questionnaires, and Doppler echocardiography. In total, 13 patients (20%) died during 4-years of follow-up; 4 patients with DS and 9 patients without DS. Mean follow-up of all patients treated with bosentan was 3.5 ± 1.2 year. We analyzed treatment efficacy separately within patients without DS (n=34) and patients with DS (n=30). Mean 6-minute walking distance (6 MWD) in patients without DS significantly increased at 6 months from 417 ± 108 to 458 ± 104 m (+41 m; p=0.002) and significant improvement continued to exist during at least 2.5 years of follow-up (p=0.003). Moreover, stroke volume increased significantly (p=0.02). In the patients with DS, 6-MWD, stroke volume and quality of life remained stable during treatment. In this study we demonstrate a prolonged beneficial effect of bosentan treatment on exercise capacity, stroke volume and quality of life in patients without DS. However the mortality rate of 20% of patients after 4 years of follow-up remains high.

The challenge of managing pulmonary arterial hypertension in adults with congenital heart disease

“…Subsequent observational studies confirmed the beneficial effect on symptoms and exercise capacity and, with a few exceptions [57,58], provided evidence that this symptomatic improvement is maintained mid-term. More recently, two studies have addressed the long-term impact of DTT in ES patients [59,60], confirming a sustained positive impact on WHO class and 6MWD in the long term. Improvement in quality of life has also been demonstrated [61].…”

Pulmonary arterial hypertension associated with congenital heart disease

“…The BREATHE-5 (Bosentan Randomised Trial of Endothelin Antagonist-5) trial and its long-term open-label extension study demonstrated the benefit of bosentan in patients with Eisenmenger's syndrome in terms of significant improvements in exercise capacity, haemodynamics and functional class compared with placebo, independently of the location of the septal defect [42][43][44]. Data from a number of studies have since confirmed these benefits in the longer term in patients with PAH-CHD and specifically in patients with Eisenmenger's syndrome [45][46][47][48][49][50]. Importantly, treatment with bosentan has been shown not to reduce systemic arterial blood oxygen saturation over short- [42] and long-term treatment [47], demonstrating that it had no negative effect on the overall shunt.…”

“…Importantly, treatment with bosentan has been shown not to reduce systemic arterial blood oxygen saturation over short- [42] and long-term treatment [47], demonstrating that it had no negative effect on the overall shunt. Treatment with bosentan has also been shown to have a positive long-term effect on QoL, a particularly important consideration for Eisenmenger's syndrome patients [49]. Despite the lack of randomised controlled trials for other PAH-specific therapies, data are available from small, open-label studies; the earliest showing treatment benefit with epoprostenol [51].…”

“…Long-term PAH-specific therapy in patients with Eisenmenger's syndrome has been shown to improve both objective exercise capacity and subjective symptoms, although escalation of therapy over time may be required if symptoms deteriorate during treatment [61]. There are also data to show that PAH-specific therapies increase QoL scores in patients with PAH-CHD [49].…”

Congenital Heart Disease and Pulmonary Hypertension

“…This benefit is more robust in patients with PAH-CHD without Down syndrome. [118][119][120][121] The predominant adverse reaction of bosentan is increased hepatic transaminases, which can be seen up to w10% of patients. 105,116 However, the distinct benefit is that it is an oral agent and simple to administer.…”