Bosentan–sildenafil association in patients with congenital heart disease-related pulmonary arterial hypertension and Eisenmenger physiology
Introduction
Congenital heart diseases (CHD) are the most common congenital malformations, accounting for about 8 cases per 1000 births [1]. A large proportion of patients with CHD with relevant systemic-to-pulmonary shunts will develop pulmonary arterial hypertension (PAH) if left untreated. Eisenmenger syndrome is defined as a congenital heart defect that initially causes chronic, large left-to-right shunt inducing severe pulmonary vascular disease and PAH, with subsequent bidirectional or reversed shunt and cyanosis, erythrocytosis and multiple organ involvement [2], [3]. Eisenmenger patients experience a poor quality of life, but as in most cases the disease progresses very slowly [4], [5] they have a considerably longer life expectancy than those with idiopathic PAH and comparable functional class [6], [7]. In fact, because of its unique haemodynamics, the right ventricle maintains its characteristics from foetal life (i.e., regression of right ventricular wall thickness does not occur), being able to compensate for the increased afterload. This is likely the reason why patients with CHD-related PAH and Eisenmenger syndrome have a better prognosis than those with other forms of PAH [8].
In recent years, new treatment strategies have largely improved the clinical status of patients with CHD-related PAH. A large randomized controlled trial [9], [10] and several single-centre, open-label studies [11], [12], [13], [14] showed that bosentan, an oral dual endothelin receptor antagonist, is effective at mid- and long-term follow-up in patients with Eisenmenger syndrome. Over the last few years, small open-label studies have suggested that sildenafil, an oral phosphodiesterase-5 inhibitor, is safe and well tolerated in adults with PAH and CHD and improves functional status and exercise capacity [15], [16], [17], [18], [19], ruling out the hypothesis that sildenafil may be detrimental to patients with CHD-related PAH and Eisenmenger syndrome because it may potentially cause a reduction in pulmonary blood flow and an increase in cyanosis [20].
Combination therapy of established PAH drugs is recommended for patients not responding adequately or deteriorating during monotherapy [21], and it has become the standard of care in many PAH centres. Bosentan and sildenafil association is the most used combination therapy all over the world [22]. Numerous case series have suggested that this drug combination appears to be safe and effective in patients with PAH [23], [24], [25], [26], but only a few single-centre reports have evaluated the safety and efficacy of this oral drug combination in patients with CHD-related PAH and Eisenmenger physiology.
The aim of this study was to evaluate the safety and efficacy of add-on oral sildenafil therapy in adult patients with CHD-related PAH and Eisenmenger syndrome after failure of oral bosentan monotherapy, by assessing its mid-term effect on clinical status, exercise capacity and haemodynamics.
Section snippets
Study design
This was a single-centre, open-label, single-arm, prospective study.
All patients with PAH associated with unoperated CHD or Eisenmenger syndrome who showed clinical deterioration on bosentan monotherapy (Tracleer®; Actelion Pharmaceuticals, Allschwil, Switzerland) were enrolled. Clinical deterioration was defined as: death from any cause, non-elective hospitalization for PAH (usually for initiation of intravenous prostanoids or lung transplantation) and/or disease progression defined as a 15%
Results
Thirty-two consecutive adult patients with PAH associated with CHD were enrolled. Twenty-eight/32 had Eisenmenger physiology and 4 (all with atrial septal defect) did not. Clinical characteristics of patients and diagnosis are shown in Table 1.
All patients were on oral bosentan therapy at recommended doses when they showed clinical worsening. In particular, 30/32 (94%) were taking bosentan 125 mg twice daily and 2/32 (6%) 62.5 mg twice daily (under-titration for oedema). In all 32 enrolled
Discussion
The main finding of our study is that addition of sildenafil in adult patients with CHD-related PAH and Eisenmenger syndrome after oral bosentan therapy failure is safe and well tolerated at 6-month follow-up, resulting in a significant improvement in clinical status, effort SpO2, exercise tolerance and haemodynamics. PAH remains a progressive disease despite improvement when using one of three medication classes: prostanoids, endothelin receptor antagonists or phosphodiesterase-5 inhibitors.
Acknowledgments
The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [37].
We express our gratitude to all the nurses of the Division of Adult Cardiology and GUCH Unit of Monaldi Hospital, for the their technical support and cooperation in the outpatient clinic and in the cath lab, particularly Mrs Assunta Carandente, Mrs Antonella Nannolo, Mrs Assunta Di Vaio, Mrs Deborah De Santis, Mrs Ada Orefice, Mrs Patrizia
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