Bosentan in pulmonary hypertension associated with fibrotic idiopathic interstitial pneumonia

Abstract

Rationale: Pulmonary hypertension (PH) associated with fibrotic idiopathic interstitial pneumonia (IIP; idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia) confers important additional morbidity and mortality.

Objectives: To evaluate the safety and clinical efficacy of the dual endothelin-1 receptor antagonist bosentan in this patient group.

Methods: In a randomized, double-blind, placebo-controlled study, 60 patients with fibrotic IIP and right heart catheter confirmed PH were randomized 2:1 to bosentan (n = 40) or placebo (n = 20). The primary study endpoint was a fall from baseline pulmonary vascular resistance index (PVRi) of 20% or more over 16 weeks.

Measurements and main results: Sixty patients (42 men; mean age, 66.6 ± 9.2 yr), with a mean pulmonary artery pressure of 36.0 (± 8.9) mm Hg, PVRi 13.0 (± 6.7) Wood Units/m(2) and reduced cardiac index of 2.21 (± 0.5) L/min/m(2) were recruited to the study. Accounting for deaths and withdrawals, paired right heart catheter data were available for analysis in 39 patients (bosentan = 25, placebo = 14). No difference in the primary outcome was detected, with seven (28.0%) patients receiving bosentan, and four (28.6%) receiving placebo achieving a reduction in PVRi of greater than or equal to 20% (P = 0.97) at 16 weeks. There was no change in functional capacity or symptoms between the two groups at 16 weeks, nor any difference in rates of serious adverse events or deaths (three deaths in each group).

Conclusions: This study shows no difference in invasive pulmonary hemodynamics, functional capacity, or symptoms between the bosentan and placebo groups over 16 weeks. Our data do not support the use of the dual endothelin-1 receptor antagonist, bosentan, in patients with PH and fibrotic IIP. Clinical trial registered with www.clinicaltrials.gov (NCT 00637065).

Trial registration: ClinicalTrials.gov NCT00637065.

Keywords: clinical trial; hypertension; interstitial lung diseases; pulmonary.

Figure 1.

CONSORT diagram. Flow diagram demonstrating the outcome of all 60 patients who consented to participate in the BPHIT trial. RHC = right heart catheter; SAE = serious adverse event.

Figure 2.

Proportion of patients with a change in pulmonary vascular resistance index of 20% from baseline. After 16 weeks, there was no difference in the percentage of patients who achieved a greater than or equal to 20% reduction in pulmonary vascular resistance index between the bosentan- and placebo-treated groups.

Figure 3.

Absolute change in pulmonary vascular resistance index (PVRi) after 16 weeks in patients treated with bosentan or placebo. After 16 weeks, there was no difference in the absolute change in PVRi between the bosentan- and placebo-treated groups.

Figure 4.

Change in arterial oxygen saturations, measured every 4 weeks, from baseline to Week 16. There was no difference in arterial oxygen saturations between the bosentan- or placebo-treated groups during the randomized phase. Bars = standard errors; solid lines = means.

Figure 5.

Analysis of response to bosentan or placebo in prespecified subgroups. Except for sex, thresholds for subgroup analyses were selected as the median value for each variable. Following study withdrawals and deaths, paired right heart catheter data were available for subgroup analysis in 39 participants (although 6-minute-walk test and Dl_CO data were not available in all patients because of inability to perform the test). CI = confidence interval; CPI = composite physiologic index; Dl_CO = diffusing capacity of carbon monoxide; mPAP = mean pulmonary artery pressure; OR = odds ratio; PVR = pulmonary vascular resistance; PVRi = pulmonary vascular resistance index.