To report outcomes in patients with CTD-pulmonary arterial hypertension (CTD-PAH) in an observational cohort treated with bosentan or sitaxentan and determine whether differences would justify a randomized, controlled multicentre study in this subpopulation.
Patients with CTD-PAH, diagnosed by right-heart catheter studies, were assigned to either bosentan or sitaxentan based on physician choice. All patients were followed up with repeat assessments and data were collected for the local registry database.
The bosentan- (n = 32) and sitaxentan- (n = 22) treated groups had comparable haemodynamic and prognostic measures at baseline. Repeat haemodynamic assessments showed reductions in pulmonary vascular resistance with bosentan (-99 dynes/s/cm(5), P < 0.01) and sitaxentan (-92 dynes/s/cm(5), P < 0.05). The 6-min walk distance improved at 3 months with sitaxentan (25 m, P < 0.05). N-terminal pro-B-type natriuretic peptide levels fell in the bosentan cohort at 6 months (-70 pmol/l, P < 0.05) and 1 year (-83 pmol/l, P < 0.01). Haemoglobin fell with both drugs (at 3 months -0.5 g/dl bosentan, P < 0.05 and -0.9 g/dl sitaxentan, P < 0.005). Calculations of the difference in treatment effect did not demonstrate superiority of either therapy. The 1-year estimated clinical worsening event rates were high: 41% sitaxentan, 62% bosentan (P = 0.142), with serious event rates of 27 and 14% (P = 0.263, log-rank test), respectively. Six patients discontinued bosentan because of transaminase elevation within the first year. Estimated 1-year survival was similar in both groups and 96% overall.
Both sitaxentan and bosentan appear effective in CTD-PAH, but the apparent additional benefit of sitaxentan reported from the open-label Sitaxentan To Relieve ImpaireD Exercise-2X study was not confirmed in this observational cohort. Although survival has improved, event rates continue to be substantial and CTD-PAH remains a therapeutic challenge.
[Show abstract][Hide abstract] ABSTRACT: Susana Hoette1,2, Dermot S O’Callaghan2, Carlos Jardim1, Rogerio Souza11Pulmonary Circulation Unit, Pulmonary Department, Heart Institute, University of São Paulo Medical School, Sao Paulo, Brazil; 2Hôpital Antoine Béclère, Université Paris Sud, Orsay, FranceAbstract: Pulmonary hypertension is characterized by an increase in mean pulmonary arterial pressure and right ventricular overload. Endothelin-1 (ET-1) is a potent vasoconstrictor with an important role in the pathogenesis of pulmonary hypertension. In addition to its vasoconstrictive action, ET-1 also stimulates cell proliferation, fibrosis, and inflammation. The blockade of both receptors involved in the action of ET-1 is beneficial in the treatment of pulmonary hypertension. The use of endothelin dual receptor blockade leads to improvements in quality of life, functional capacity, and pulmonary hemodynamics in affected patients. This article reviews the importance of ET-1 in the pathogenesis of pulmonary hypertension and demonstrates the benefits of blockage of the action of ET-1 in this disease.Keywords: pulmonary hypertension treatment, endothelin-1, endothelin receptor blockage, bosentan
Journal of Receptor, Ligand and Channel Research 01/2010;
[Show abstract][Hide abstract] ABSTRACT: Pulmonary arterial hypertension (PAH) is a devastating vascular complication of a number of connective tissue diseases, including
systemic sclerosis (SSc), where it has a dramatic impact on the clinical course and overall survival and is the single most
common cause of death in patients afflicted with this syndrome. Although remarkable advances have been achieved in elucidating
the pathogenesis of PAH over the past two decades, leading to the development of disease-targeted therapies for the idiopathic
form of this condition (IPAH), the response to therapy is suboptimal in SSc-related PAH (SSc-PAH), and survival remains very
poor. Factors accounting for striking clinical and prognostic differences between these two syndromes are unclear but may
include a more pronounced inflammatory response and a higher prevalence of comorbidities in SSc-PAH. Furthermore, currently
available markers of disease severity and clinical tools to assess response to therapy, which may be reliable in IPAH, are
either limited or lacking in SSc-PAH. Thus, a more focused approach, including a better understanding of the pathogenesis
and genetic factors underlying the development of SSc-PAH, a search for more specific and reliable tools to adequately assess
functional impairment and monitor therapy, as well as the design of novel targeted therapies, are all urgently required to
alter the dismal course of this syndrome.
KeywordsSystemic sclerosis-Pulmonary arterial hypertension-Systemic sclerosis-related pulmonary arterial hypertension
Case Studies in Systemic Sclerosis, 08/2011: pages 127-137;
[Show abstract][Hide abstract] ABSTRACT: It is now well appreciated that pulmonary hypertension is a frequent complication of scleroderma and that it occurs in both of the major disease subsets. However, despite a much greater understanding of the different forms of pulmonary hypertension and the availability of effective treatments for different forms of this disease, it remains one of the most feared complications of scleroderma. Compared with other forms of PAH that occur in scleroderma has a significantly worse outcome, and this is especially in comparison with idiopathic PAH. Thus, the strategies that are used for PAH may need to be modified in the context of scleroderma, and this is discussed below.
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