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Bosentan in Pulmonary Hypertension Associated with Fibrotic Idiopathic Interstitial Pneumonia: The BPHIT Study

Corte TJ, Keir GJ, Dimopoulos K, Howard L, Corris PA, Parfitt L, et al. American Journal of Respiratory and Critical Care Medicine 2014; 190:208-217

Background: Pulmonary hypertension (PH) is strongly linked to morbidity and mortality in fibrotic idiopathic interstitial pneumonia (IIP; includes idiopathic pulmonary fibrosis [IPF] and nonspecific interstitial pneumonitis [NSIP]). It is not well described if treating these patients with PH-specific medications would improve outcomes. While uncontrolled studies and post hoc analyses have suggested that treating IIP-PH may be beneficial, this is the first placebo-controlled, blinded, randomized study.

Methods:  This was a 16-week, double-blind, placebo-controlled trial randomizing patients with IIP-PH to bosentan or placebo (in a 2:1 ratio) conducted at 8 specialty centers in the UK.  Enrolled participants had a diagnosis of IPF or idiopathic fibrotic NSIP made by multispecialty consensus at specialized IIP centers and PH, defined as a mean pulmonary artery pressure (mPAP) of ≥25mmHg and a left ventricular end-diastolic pressure or pulmonary capillary wedge pressure of ≤15mmHg.  Study drug, either bosentan (62.5mg titrated up to 125mg) or placebo, was given twice per day for 16 weeks.  The primary endpoint was a categorical fall from baseline pulmonary vascular resistance index (PVRi) of 20% or more over 16 weeks. Secondary endpoints included changes in hemodynamics, 6-minute walk test, WHO functional class, quality of life, lung function, oxygen saturation, BNP, echo parameters, and disease progression.  The study was powered to detect a difference between group proportions of 0.29 (1% of the placebo group and 30% of the treatment group meeting the PVRi change cutoff).  Only patients alive and getting a right heart catheterization at 16 weeks were included in the primary analysis.

Results: Of the original 60 patients included, 39 were evaluable at 16 weeks (25 bosentan, 14 placebo).  There was no difference in the primary outcome between the two groups; 28% of patients in the bosentan group achieved a 20% reduction in PVRi, compared to 28.6% in the placebo group (p=0.97).  There were no statistically significant differences in any of the secondary outcomes, including hemodynamics, 6-minute walk distance, quality of life, echocardiogram parameters, BNP, or disease progression. There was no difference between groups in resting oxygen saturation or need for supplemental oxygen after 16 weeks.  There were no subgroups identified that had a more favorable change in PVRi with bosentan.

Conclusions: Although bosentan appeared to be safe when taken for 16 weeks in patients with IIP-PH, it did not lead to significant improvements in pulmonary hemodynamics, exercise capacity, quality of life, or BNP. 

Expert Commentary: The treatment of IIP remains a challenge for clinicians and in particular, IIP complicated by PH, the frequency of which increases with disease severity.  No randomized, placebo-controlled studies to date have clearly demonstrated improved hemodynamics in this group of individuals when treated with drugs indicated for PAH such as prostacyclins, phosphodiesterase-5 inhibitors, endothelin receptor antagonists and guanylate cyclase stimulators although clinicians have certainly tried using these agents in individual cases, particularly when the degree of PH appears to be “out of proportion” to the severity of lung disease.  Studies done to date include an open label study of sildenafil in IPF demonstrating improvement in walk distance in the majority; a post-hoc analysis of a placebo-controlled trial of sildenafil in IPF demonstrating improvements in walk distance for those with RV dysfunction;  an open-label study of riociguat in PH-ILD demonstrating improvements in cardiac output, pulmonary vascular resistance and six minute walk distance but not mean pulmonary artery pressure; and an open label study of bosentan in IPF demonstrating no clinically relevant changes in gas exchange.  The study presented here represents the most rigorously conducted trial to date including patients with known IPF or fibrotic NSIP and PH defined on RHC randomized in a 2:1 fashion to bosentan vs. placebo for 16 weeks.  Unfortunately, no significant difference in invasive pulmonary hemodynamics, symptoms or exercise capacity was demonstrated.  The authors of this study are to be applauded for attempting such a study given the inherent difficulties of recruiting such a sick patient population.  Unfortunately, the sample size of the study is small to begin with and patient attrition during the study is high.  Having said that, we do not even see a trend suggesting improvement in the treatment group.  While these data are certainly discouraging, the possibility that another agent might be beneficial or that a more highly selected subgroup such as those with PH “out of proportion” to the degree of lung disease might still benefit is unanswered in this study.  More data will be needed to answer these questions.

Article summary by: Matthew R. Lammi, MD; Assistant Professor of Medicine, Louisiana State University Health Sciences Center

Expert commentary by: MeiLan K. Han, MD, MS; Associated Professor of Medicine, University of Michigan

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Last Reviewed: September 2016