Potential benefit of bosentan therapy in borderline or less severe pulmonary hypertension secondary to idiopathic pulmonary fibrosis—an interim analysis of results from a prospective, single-center, randomized, parallel-group study

Abstract

BackgroundNo drugs have been approved for the treatment of patients with pulmonary hypertension (PH) secondary to idiopathic pulmonary fibrosis (IPF), particularly those with idiopathic honeycomb lung. This study was conducted to investigate the long-term efficacy and safety of bosentan for PH based on changes in prognosis and respiratory failure.MethodsIPF patients with borderline or less severe PH and completely organized honeycomb lung were randomized (1:1) to bosentan or no treatment for PH for 2 years and assessed at baseline and every 6 months for respiratory failure, activities of daily living (ADL), lung and heart functions by right cardiac catheterization, and other parameters. An interim analysis was performed, however, following detection of a significant survival benefit favoring bosentan therapy.ResultsSignificant differences were noted for the bosentan-treated (n = 12) vs. untreated (n = 12) groups in hospital-free survival (603.44 ± 50.074 days vs. 358.87 ± 68.65 days; hazard ratio [HR], 0.19; P = 0.017) and overall survival (671 days vs. 433.78 ± 66.98 days; HR, 0.10; P = 0.0082). Again, significant improvements were noted for the bosentan-treated group from baseline to month 6 or 12 in several indices in ADL, pulmonary circulation, and %DLCO. Without requiring O2 inhalation, bosentan was associated with no increase but a trend toward a decrease in adverse events and an improvement in respiratory status.ConclusionsBosentan tended to improve prognosis and ADL without worsening respiratory failure in IPF patients with borderline or less severe PH and completely organized honeycomb lung alone.Trial registrationThis study was registered on December 18, 2010 with UMIN-CTR Clinical Trial as UMIN000004749 to investigate the long-term influence of bosentan on cardiac function, as well as its cardioprotective efficacy and safety, in patients with pulmonary hypertension secondary to concurrent COPD and IPF, respectively.Electronic supplementary materialThe online version of this article (doi: 10.1186/s12890-017-0523-2) contains supplementary material, which is available to authorized users.

The Clinical Efficacy of Pulmonary Hypertension-Specific Agents in Idiopathic Pulmonary Fibrosis: Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials

“…Although one RCT did report decreased all-cause mortality to end of study, its results were limited by a small sample size and high risk of bias. 26 The current findings of our pooled estimates might be explained in the following ways. 1) The development of IPF-associated PH can be explained by hypoxemia-induced vascular remodeling, IPF-specific hyperplasia and fibrosis of the elastic lamina of small pulmonary arteries, in situ thrombosis in small pulmonary arteries, intimal proliferation and fibrosis of the pulmonary venules, and various IPF-mediated cytokine effects.…”

“…One study had a significantly different all-cause mortality estimate than the others. 26 Even after excluding that study, 26 however, all-cause mortality did not differ significantly between the groups, although the heterogeneity decreased (HR, 0.99; 95% CI, 0.92, 1.06; P = 0.78; I 2 = 0%). We found no evidence of publication bias using Begg's (P = 0.266) and Egger's (P = 0.516) tests.…”

“…outcome that could be combined in this meta-analysis. 14,15,[24][25][26][27][28][29][30][31] Individual characteristics of the selected studies are shown in Table 1. All included articles were published between 2008 and 2018.…”

Management of PH-ILD: Past, Present, and Future

“…16 In contrast, interim results from a small open-label study suggested bosentan improved hemodynamics and survival in patients with exercise or mild-moderate PH and IPF without parenchymal inflammation. 17 As the inclusion of only stable lung disease minimized confounding from respiratory exacerbations, it was suggested this may more accurately reflect the effect of bosentan on the pulmonary vasculature.…”

Heart‑lung crosstalk in pulmonary arterial hypertension following myocardial infarction (Review)

“…However, two drugs appear to be somewhat effective, namely the dual (ET A and ET B ) ET receptor antagonist bosentan and the selective ET receptor antagonist ambristan. However, their efficacy is restricted by their limited ability to penetrate tissue ( 37 - 39 ). Expression of ET-1 is mainly detected in the ECs of the pulmonary artery and may lead to intimal fibrosis and thickening of the media.…”