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

Background: No 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.

Methods: IPF 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.

Results: Significant 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.

Conclusions: Bosentan 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 registration: This 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.

Keywords: Echocardiography; Endothelin receptor antagonists; Idiopathic pulmonary fibrosis; Pulmonary hypertension; Right heart catheterization.

Fig. 1

Patient flowchart

Fig. 2

Analysis of survival by adverse event. a Analysis of the time to exacerbation of subjective dyspnea. Among the untreated patients with borderline or less severe PH, the time to exacerbation of dyspnea was 152.00 ± 89.94 days (mean ± SD) in 7 of 12 patients confirmed to have experienced exacerbation of subjective symptoms of dyspnea by the data obtained on the cut-off date. Among the drug-treated patients with borderline or less severe PH, the time to exacerbation of dyspnea was 259.00 ± 49.87 days (mean ± SD) in 3 of 12 patients confirmed to have experienced exacerbation of dyspnea by the data obtained on the cut-off date. Proportional hazard analysis showed that the risk ratio of the drug-treated to untreated groups was 0.58, but with no significant difference noted. The time to exacerbation of dyspnea at the time of analysis was 218.17 ± 35.62 days (mean ± SE) in the untreated group and 290.71 ± 12.036 days in the drug-treated group, but with no significant difference noted. b Analysis of the time to an increase in the dose of O₂ (event). Increase of the O₂ dose: In the untreated patients with borderline or less severe PH, the time to the dose increase was 199.00 ± 132.90 days (mean ± SD) in 5 of 12 patients confirmed to have required an increase of the dose of O₂ by the data obtained on the cutoff date. In the drug-treated patients with borderline or less severe PH, the time to the dose increase was 335.00 ± 182.43 days (mean ± SD) in 3 of 12 patients confirmed to have required an increase of the O₂ dose based on the data obtained on the cut-off date. The risk ratio analysis showed that the hazard ratio of the drug-treated to untreated groups was 0.58. The time to O₂ dose increase at the time of analysis was 357.71 ± 50.83 days in the untreated group and 438.20 ± 34.61 days in the drug-treated group with no significant difference between the groups, despite the results favoring the drug-treated group. In addition, only 1 drug-treated patient with borderline or less severe PH achieved a decrease of the O₂ dose on day 243 due to an improvement of respiratory function. c Hospital-free survival. Of the 12 untreated patients with borderline or less severe PH, 8 were confirmed to have been hospitalized (event) by the data obtained on the cut-off date with the time to hospitalization being 241.50 ± 192.24 days (mean ± SD). Of the 12 drug-treated patients with borderline or less severe PH, 2 was confirmed to have been hospitalized by the data obtained on the cut-off date with the time to hospitalization being 239.002 ± 169.00 days. At the time of survival time analysis, hospital-free survival in the untreated group was 358.87 ± 68.65 days (mean ± SE) (median, 331 days), which was shown to be significantly different from that in the drug-treated group (603.44 ± 50.074) by proportional hazard analysis (hazard ratio [HR] of the drug-treated to untreated groups, 0.10; P = 0.017). d Overall survival. Of the 12 untreated patients with borderline or less severe PH, 7 were confirmed dead (event) by the data obtained on the cut-off date with the time to event being 309.29 ± 195.13 days (mean ± SD); of the drug-treated patients with borderline or less severe PH, 1 was confirmed dead by the data on the cut-off date with the time to event being 671 days. At the time of survival analysis, the time to event in the untreated group was 433.78 ± 66.98 days (mean ± SE), which was significantly different from that in the drug-treated group by proportional hazard analysis (HR of the drug-treated to untreated groups, 0.10; P = 0.0082)

Fig. 3

Results of RHC. a Comparison of changes in mPAP from baseline to month 6 between untreated and drug-treated patients with borderline or less severe PH. b Comparison of change in PVR from baseline to month 6 between untreated and drug-treated patients with borderline or less severe PH. Significant differences were seen between the untreated and drug-treated patients with borderline or less severe PH with regard to changes in mPAP, and PVR from baseline to month 6 (untreated vs. drug-treated: mean difference in mPAP, 4.71 vs. -2.60 mmHg, P = 0.0035; PVR, +1.60 vs. -0.69 woods, P = 0.0020)