Eisenmenger syndrome (ES) is defined as significant pulmonary arterial hypertension (PAH) in conjunction with congenital heart disease (CHD) and shunt reversal,1 and comprises about 1% of all CHD.2 Although caused by a defect in the heart, ES is a multiorgan disorder associated with numerous life-threatening complications, including hemoptysis, cerebrovascular accidents, brain abscesses, arrhythmias and syncope.3 The majority of patients who develop ES survive to adulthood, but markedly diminished exercise tolerance with reduced life expectancy is the rule.4 Although their survival is better than in idiopathic pulmonary arterial hypertension (IPAH), ES patients share many histopathological similarities with IPAH.5

These similarities made the use of pulmonary vasodilators in this subset of patients an attractive option. In the BREATHE-5 study, the first placebo-controlled trial in patients with ES, the endothelin-receptor antagonist (ETRA) bosentan was well tolerated and improved exercise capacity and hemodynamics without compromising peripheral oxygen saturation,6 and these results were further supported by the open-label extension of this pivotal trial.7 However, BREATHE-5 only included ES patients with simple CHD (atrial septal defect, ventricular septal defect or both), excluding patients with complex CHD, patent ductus arteriosus or segmental pulmonary hypertension as in pulmonary atresia. Evidence for the use of bosentan in this patient subset is only available in the form of series with small samples or short follow-up.8–10 Moreover, due to the progressive nature of the disease,6 some patients may still have a negative evolution even though treated with advanced therapies, highlighting the need for combination therapy. In the only randomized controlled trial on combination therapy in ES, the addition of sildenafil to ongoing bosentan failed to improve walking distance or pulmonary vascular resistance.11

The aims of our study were (i) to assess the safety of bosentan and its short-term effects on systemic oxygen saturation and exercise capacity in patients with complex CHD and PAH, and (ii) to perform a long-term follow-up to assess efficacy and safety of bosentan treatment and the need for combination therapy in this group of complex CHD patients.

In patients with PAH and complex CHD, bosentan was a safe, well tolerated and effective therapy. The effects on 6MWT were evident after six months and were sustained in long-term follow-up. The safety and drug tolerance were similar to those reported in the IPAH and BREATHE-5 studies, with no serious side effects occurring during this long follow-up period.

Patients with PAH and complex CHD have a better long-term prognosis than those with IPAH,13 mainly due to preservation of biventricular function until the later stages of disease. Some authors suggest that the right ventricle is ‘primed’ for a lifetime of functioning at systemic level pressure, with persistence of a protective fetal morphology.14 Unfortunately, and in contrast to previous claims that the hemodynamics of patients with ES was stable over time, the BREATHE-5 study demonstrated that even in a limited 16-week follow-up, indicators of progressive vascular disease, such as pulmonary vascular resistance index, worsened in the placebo group.6

The available evidence regarding the use of disease-targeting therapies has recently been reviewed elsewhere.15 The pivotal role of endothelin-1 in the development of pulmonary vasculopathy made the use of ETRA attractive and several studies, including one randomized controlled trial, established the benefit of ETRA in ES patients with simple defects.3,5 The evidence for sildenafil or prostacyclins is based on smaller studies.9 However, BREATHE-5 excluded patients with complex CHD and a recent single-center, randomized placebo-controlled study with 21 patients had only one patient with complex disease. Although it was thought that the location of the shunt (pre-tricuspid versus post-tricuspid) would influence treatment outcomes,16 a subgroup analysis of the BREATHE-5 study and two recent reports do not support this hypothesis.9,17 Moreover, a comparison of patients with persistent PAH after shunt closure and ES patients found no differences in four-year survival.17

After the use of bosentan, we noted a significant improvement in exercise capacity and in WHO functional class, with no decrease in Borg dyspnea score, indicating that these patients increased their exercise capacity with a similar level of perceived dyspnea. Moreover, mean six-month improvement in 6MWD was 56 m, similar to other reports, including patients with non-complex disease15 and with IPAH.5 Our results reproduce, in a larger population, the findings of Diaz-Caraballo et al., the only study to date focusing solely on complex congenital heart disease. In that study, mean 6MWD improved significantly at six months (from 266±161 to 343±121 m, p=0.045), the change being maintained at two years.8 We extend these findings to a four-year follow-up.

We also included pulmonary atresia patients, a distinct subgroup, as they present with segmental pulmonary hypertension and no shunt reversal. Little evidence is available regarding the role of pulmonary vasodilators in these patients. A recent report by Schuuring et al. on seven patients demonstrates a 62-m improvement in 6MWD after one year of bosentan treatment.10 Our results are similar, with a significant improvement in walking distance at six months, sustained in the long term. Interestingly, none of the patients needed combination therapy. The mechanism whereby bosentan acts on this subset of patients is not known, but may be related to its action on the endothelin pathway.

Although not evidence-based but in line with recommendations for IPAH,5 combination therapy with sildenafil was initiated in four patients due to disease progression, reflecting the high-risk group that was studied and the progressive nature of the disease during long-term follow-up. It is noteworthy that the four patients who underwent therapeutic escalation remained clinically stable for almost four years before the initiation of sildenafil.

Patients with PAH and complex CHD are at high risk of death18 but there is a paucity of data regarding survival in such patients under vasodilator therapy. In our cohort, total mortality was 14% at four years, which is higher than in the series by Dimopoulos et al.19 (around 3% at two years), lower than that reported by Vis et al.17 (20% at four years), but similar to the recently published results by Monfredi et al.20 Differences in study design, follow-up duration and population selection may be responsible for these disparities.

The safety of bosentan in this high-risk population was remarkable. No patient experienced a rise in liver enzymes exceeding three times the upper limit of normal or systemic hypotension. Only one patient discontinued bosentan due to lower limb edema. Moreover, and in line with previous reports, no changes were noted in systemic oxygenation. This may be due to the limited influence of bosentan on the net right-to-left shunt because its effects on both pulmonary and systemic vascular resistance are similar.6

This was a non-randomized, single-center study, with a limited number of patients reflecting the rarity of this condition. It represents a cohort of patients being followed in a specialized pulmonary hypertension clinic. Our small sample precludes further comparisons between different types of congenital defects. Although only patients with right heart catheterization-confirmed pulmonary hypertension were included in this study, the heterogeneity of the congenital lesions causing it may have influenced clinical evolution, themselves affecting the outcome. An example is truncal valve regurgitation in truncus arteriosus patients; both patients who died had severe regurgitation that may have contributed to their dismal prognosis. Several factors can influence exercise capacity in ES patients, including iron status,21 associated cardiac lesions or pulmonary comorbidities; however, our results regarding exercise capacity and functional status were consistent with other studies in patients without complex congenital disease, suggesting that bosentan has a true therapeutic effect; all patients had regular iron status assessments and correction as needed. We did not perform hemodynamic re-evaluation of patients after pulmonary vasodilator therapy; all clinical decisions regarding therapeutic escalation were made in the light of clinical, laboratorial, echocardiographic and functional data.

Bosentan was safe and was associated with improved exercise capacity in patients with complex congenital heart disease and PAH. The improvement in exercise capacity was maintained up to four years and the longer-term safety profile was similar to that reported in simple congenital heart disease patients.

Graça Castro and António Marinho da Silva are consultants for Actelion Portugal. Rui Baptista has received funding for research from Actelion Portugal. Pedro Monteiro and Luís Augusto Providência have no relationships relevant to the contents of this paper to disclose.