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Original Research: Pulmonary Vascular Disease |

Bosentan for Sarcoidosis-Associated Pulmonary HypertensionBosentan for Sarcoiodosis Pulmonary Hypertension: A Double-Blind Placebo Controlled Randomized Trial FREE TO VIEW

Robert P. Baughman, MD, FCCP; Daniel A. Culver, DO, FCCP; Francis C. Cordova, MD; Maria Padilla, MD; Kevin F. Gibson, MD; Elyse E. Lower, MD; Peter J. Engel, MD
Author and Funding Information

From the Department of Internal Medicine (Drs Baughman and Lower), University of Cincinnati Medical Center, Cincinnati, OH; Cleveland Clinic Foundation (Dr Culver), Cleveland, OH; Department of Internal Medicine (Dr Cordova), Temple University, Philadelphia, PA; Department of Medicine (Dr Padilla), Icahn School of Medicine at Mount Sinai, New York, NY; Division of Pulmonary, Allergy, and Critical Care Medicine (Dr Gibson), University of Pittsburgh, Pittsburgh, PA; and The Christ Hospital (Dr Engel), Cincinnati, OH.

Correspondence to: Robert P. Baughman, MD, FCCP, Department of Medicine, University of Cincinnati Medical Center, 1001 Holmes, Eden Ave, Cincinnati, OH 45267-0565; e-mail: bob.baughman@uc.edu


Funding/Support: This study was supported by Actelion Pharmaceuticals US, Inc.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(4):810-817. doi:10.1378/chest.13-1766
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Background:  Sarcoidosis-associated pulmonary hypertension (SAPH) is a common problem in patients with persistent dyspneic sarcoidosis. The objective of this study was to determine the effect of bosentan therapy on pulmonary arterial hemodynamics in patients with SAPH.

Methods:  This 16-week study was a double-blind, placebo-controlled trial of either bosentan or placebo in patients with SAPH confirmed by right-sided heart catheterization. Patients were enrolled from multiple academic centers specializing in sarcoidosis care. They were stable on sarcoidosis therapy and were receiving no therapy for pulmonary hypertension. The cohort was randomized two to one to receive bosentan at a maximal dose of 125 mg or placebo bid for 16 weeks. Pulmonary function studies, 6-min walk test, and right-sided heart hemodynamics, including pulmonary artery mean pressure and pulmonary vascular resistance (PVR), were performed before and after 16 weeks of therapy.

Results:  Thirty-five patients completed 16 weeks of therapy (23 treated with bosentan, 12 with placebo). For those treated with bosentan, repeat hemodynamic studies at 16 weeks demonstrated a significant mean ± SD fall in PA mean pressure (−4 ± 6.6 mm Hg, P = .0105) and PVR (−1.7 ± 2.75 Wood units, P = .0104). For the patients treated with placebo, there was no significant change in either PA mean pressure (1 ± 3.7 mm Hg, P > .05) or PVR (0.1 ± 1.42 Wood units, P > .05). There was no significant change in 6-min walk distance for either group. Two patients treated with bosentan required an increase of supplemental oxygen by > 2 L after 16 weeks of therapy.

Conclusions:  This study demonstrated that bosentan significantly improved pulmonary hemodynamics in patients with SAPH.

Trial registry:  ClinicalTrials.gov; No: NCT00581607; URL: www.clinicaltrials.gov

Figures in this Article

Bosentan has been shown to be more effective than placebo in reducing pulmonary artery (PA) pressure in pulmonary arterial hypertension.1 The drug has become a standard therapy for mild to moderately severe World Health Organization (WHO) group 1 pulmonary hypertension.2,3 The use of endothelin receptor antagonists to treat group 1 pulmonary arterial hypertension has led to an overall improved survival in this group.4

Sarcoidosis-associated pulmonary hypertension (SAPH) is placed in group 5 of the current WHO classification system.5 It may be found in a significant number of patients with persistent dyspnea.68 The presence of pulmonary hypertension in patients with advanced pulmonary sarcoidosis is associated with increased mortality.6,9 Several case series have suggested that treatment of pulmonary arterial hypertension with vasoactive drugs may reduce the level of pulmonary hypertension,1013 including in patients treated with bosentan alone or with other treatments.12,14,15 To determine whether bosentan was effective in treating SAPH, we performed a double-blind, placebo-controlled trial of the agent.

Patients aged 18 to 90 years with sarcoidosis defined by standard criteria16 were eligible for consideration. The patients were included if they had documented pulmonary hypertension with a PA mean pressure ≥ 25 mm Hg as measured by cardiac catheterization within 6 months of entry into the study. Pulmonary artery occlusion pressure (PAOP), left ventricular end-diastolic pressure, or both was < 15 mm Hg. Patients had to exhibit New York Heart Association (NYHA) functional class II or III symptoms. They had to have a 6-min walk distance (6MWD) of 100 to 500 m and a < 10% difference in the 6MWD performed on two separate occasions before receiving the first dose of bosentan. All patients were on stable immunotherapy for sarcoidosis, including prednisone, methotrexate, azathioprine, hydroxychloroquine, cyclophosphamide, thalidomide, and infliximab, for 3 months prior to the first dose of drug.

Patients were excluded from the study if they had received specific therapy for pulmonary hypertension within 28 days of screening. The one exception was that patients who had been on a stable dose of calcium channel blocker for > 1 month prior to right-sided heart catheterization were allowed to continue the medication. Patients were excluded if they had severe airway obstruction as defined by FEV1/FVC < 35%; had an exercise limitation consistent with NYHA functional class IV; were pregnant or breast feeding; had significant left ventricular dysfunction (left ventricular ejection fraction < 35%); had a cardiac index < 2.0 L, right atrial pressure > 15 mm Hg, or both; had significant liver dysfunction not due to sarcoidosis; had other severe organ disease believed by the investigators to affect survival during the course of the study; were unable to perform the 6-min walk test (6MWT) at the time of screening; or were receiving either cyclosporine or glyburide. All patients provided written informed consent of an institutional review board-approved protocol (University of Cincinnati Institutional Review Board #7-3-22-1).

Before the first evaluation, patients underwent two 6MWTs using a standardized protocol.17 Patients using supplemental oxygen as part of their standard care were maintained on the same level of oxygen. We recorded the oxygen flow rate as well as the oxygen saturation at rest and with exercise. Patients were believed to have significant oxygen desaturation if their lowest oxygen saturation was > 5% of rest value or if they required an increase in supplemental oxygen of at least 2 L/min. We measured FVC, FEV1, and the FEV1/FVC ratio. Percent predicted normal values were calculated with reference equations from the National Health and Nutrition Examination Survey.18

Procedure

Patients were block randomized at each institution to receive either drug or placebo at a 2:1 ratio. Randomization was performed with a computer program, and the drug was supplied from a central institution (University of Cincinnati). For the first month, the patients received either 62.5 mg bosentan or placebo bid. After 1 month, a liver function test was performed. If stable, the dose was increased to 125 mg or two placebo tablets bid. Liver function testing was repeated monthly.

After 16 weeks, PA systolic, diastolic, and mean pressures and PAOP were measured. Cardiac output was determined by thermodilution method, and the pulmonary vascular resistance (PVR) was calculated. We did not collect cardiac output data as determined by the Fick method. Patients also underwent repeat pulmonary function testing, including spirometry and 6MWT.

Statistical Analysis

The predefined end point of the study was a change in PA mean pressure after 16 weeks of bosentan or placebo treatment. The sample size was based on the inhaled iloprost study.10 In that study, patients with sarcoidosis prior to therapy had a mean ± SD PVR of 5.8 ± 4.669 Wood units. A sample size of 38 patients would provide 80% power to detect 50% difference in PVR between the two groups. The various measurements followed a normal distribution, and comparison within and between groups based on therapy was performed with Student t test. On the basis of a prior study,12 a subgroup analysis of patients with an FVC ≤ 50% predicted vs those with a higher FVC was performed. Comparisons were again performed with Student t test, and linear correlation was calculated in some cases. P < .05 was considered significant.

Forty-three patients from five sites were enrolled in the study over a 4-year period, ending in September 2011. Figure 1 summarizes the outcomes for these patients. Four patients were never randomized because of withdrawn consent (two patients) or ineligibility (one each for liver dysfunction and NYHA functional class IV). Of the 39 randomized patients, 35 completed 16 weeks of therapy. Five patients declined repeat right-sided heart catheterization but continued in the study. One patient had a repeat catheterization but could not perform the repeat 6MWT because of an above-knee amputation due to peripheral vascular disease. Patients with missing data were excluded from analysis.

Figure Jump LinkFigure 1. Flow chart demonstrating the outcome of all 43 patients who consented to participate in the clinical trial.19 Thirty-nine patients were randomized to receive either bosentan or placebo. Four patients stopped the study drug before week 8. Five patients did not undergo repeat RHC. One patient in the placebo group had repeat RHC but was unable to repeat the 6MWT because of an above-knee amputation before week 16. 6MWT = 6-min walk test; pts = patients; RHC = right-sided heart catheterization.Grahic Jump Location

The clinical features of the 35 patients who completed the full 16 weeks of the study are summarized in Table 120 by the CONSORT (Consolidated Standards of Reporting Trials) method.19 There was no significant difference between the two groups. There was no difference in the baseline features of these 35 patients and the remaining eight who enrolled in the study but did not complete the 16 weeks of treatment. Approximately one-half of the patients in both groups had an FVC < 60% predicted, and one-half had Scadding stage IV chest radiographs. There was no difference in FVC or 6MWD at baseline between the two treatment groups. All but two patients (one from each group) were receiving one or more systemic therapies for sarcoidosis.

Table Graphic Jump Location
Table 1 —Clinical Features of Study Patients

Data are presented as mean ± SD or counts. 6MWD = 6-min walk distance; NYHA = New York Heart Association.

a 

Eighteen patients in the bosentan group and nine patients in the placebo group used prednisone.

b 

Patients could be receiving more than one therapy.

c 

Includes one patient not taking prednisone or receiving other therapy.

Table 2 summarizes the initial hemodynamic values measured during right-sided heart catheterization. Patients who were randomized to the placebo arm had lower PA systolic pressure (P < .05). This difference was small, and no significant difference was found between the two groups for any other hemodynamic value, including PA mean pressure and PVR, the two parameters analyzed in this study. Hemodynamic values at week 16 are also shown in Table 2. For the bosentan group, there was a significant fall in the PA systolic and mean pressures as well as the PVR. No significant change after treatment of the PA diastolic or wedge pressure, cardiac output, or cardiac index was seen. For the placebo group, there was no significant difference for any hemodynamic parameter.

Table Graphic Jump Location
Table 2 —Hemodynamic Values From Right-Sided Heart Catheterization Initially and After 16 Wk of Therapy

Data are presented as mean ± SD. PA = pulmonary artery; PAOP = pulmonary artery occlusion pressure; PVR = pulmonary vascular resistance.

a 

Differs from baseline, P < .05.

b 

Differs from bosentan group, P < .05.

c 

Differs from baseline, P < .02.

d 

Differs from baseline, P < .02.

The primary end point of the study was the change in PA mean pressure with either bosentan or placebo. Figure 2A demonstrates a significant drop in the PA mean pressure for patients treated with bosentan (baseline, 36 ± 7.1 mm Hg; 16 weeks, 32 ± 8.8 mm Hg; P < .02). Four patients experienced a rise in the PA mean pressure (1, 5, 8, and 10 mm Hg) during the 16 weeks of therapy. Two of these four patients had an FVC < 50% and fibrosis on their chest radiographs. Figure 2B demonstrates no significant change in the PA mean pressure for patients treated with placebo (baseline, 30 ± 4.1 mm Hg; 16 weeks, 31 ± 6.3 mm Hg; P > .05). After 16 weeks of therapy, PA mean pressure fell significantly for the bosentan vs the placebo group (−4 ± 6.6 mm Hg vs 1 ± 3.7 mm Hg, respectively; P < .05). Figure 3A demonstrates a significant drop in PVR for patients treated with bosentan (baseline, 6.1 ± 2.97 Wood units; 16 weeks, 4.4 ± 2.03 Wood units; P < .02). Figure 3B shows no significant change in PVR in the placebo group (baseline, 4.0 ± 2.07 Wood units; 16 weeks, 4.2 ± 2.17 Wood units; P > .05). The fall in PVR in patients treated with bosentan (−1.7 ± 2.75 Wood units) was not significantly different from the rise in PVR for those treated with placebo (0.1 ± 1.42 Wood units, P > .05). A small, but not significant difference in the percent change in PVR was seen for the bosentan vs placebo groups (−21.6% ± 0.344% vs 10.1% ± 0.500%, P = .0534).

Figure Jump LinkFigure 2. A, PA mean before and after 16 wk of bosentan therapy. There was a significant fall in PA mean pressure (−4 ± 6.6 mm Hg, P < .02). B, PA mean before and after 16 wk of placebo therapy. There was no significant change in PA mean pressure (1 ± 3.7 mm Hg, P > .05). PA = pulmonary artery.Grahic Jump Location
Figure Jump LinkFigure 3. A, PVR before and after 16 wk of bosentan therapy. There was a significant fall in PVR (−1.7 ± 2.75 Wood units, P < .02). B, PVR before and after 16 wk of placebo therapy. There was no change in PVR (0.1 ± 1.42 Wood units, P > .05). PVR = pulmonary vascular resistance.Grahic Jump Location

No significant difference in the 6MWD was found for either the bosentan group (baseline, 343 ± 95.5 m; 16 weeks, 320 ± 75.3 m; P > .05 by Student paired-sample t test) or the placebo group (baseline, 313 ± 72.6 m; 16 weeks, 331 ± 70.3 m; P > .05). Over the 16 weeks of the study, the 6MWD fell for the bosentan group (−23 ± 69.5 m) but rose for the placebo group (17 ± 44.1 m) (Fig 4). The difference between the two groups was not significant. Two patients in the bosentan group had a large drop in 6MWD at 16 weeks. One patient, who had a 173-m drop in 6MWD, had a baseline FVC of 36% predicted. The other patient, who had a 213-m drop in 6MWD, had a baseline FVC of 73% predicted. Both patients had a > 5-mm Hg drop in PA mean pressure with therapy. At the time of the 16-week evaluation, the second patient was recovering from an acute respiratory infection. About one-half of the patients had significant oxygen desaturation during the 6MWT. After 16 weeks of therapy, clinically significant oxygen desaturation developed in more during the 6MWT, but there was no difference between the rate of oxygen desaturation between the placebo and bosentan arms (Table 3). Only two patients had supplemental oxygen increased by > 2 L after 16 weeks of therapy (both treated with bosentan). One patient had a mild increase in PA mean pressure at week 16 while the other had no change in pressure. After 16 weeks of therapy, no significant difference in the FVC was seen for either the bosentan group (baseline, 2.00 ± 0.685 L; 16 weeks, 1.94 ± 0.694 L; P > .05) or the placebo group (baseline, 1.89 ± 0.928 L; 16 weeks, 1.97 ± 0.927 L; P > .05).

Figure Jump LinkFigure 4. Change in 6MWD after 16 wk of either bosentan or placebo therapy. There was no significant difference between the two treatment groups. 6MWD = 6-min walk distance.Grahic Jump Location
Table Graphic Jump Location
Table 3 —Rate of Desaturation During 6MWT

Data are presented as No. positive/total No. (%). Oxygen desaturation defined as either a > 5% decrease in lowest oxygen saturation compared with rest, increase in oxygen supplementation of > 2 L/min, or both. 6MWT = 6-min walk test.

a 

One patient was unable to do the 6MWT at week 16 because of above-knee amputation.

For patients treated with bosentan, we compared the change in pulmonary hemodynamics and 6MWD of the 10 with an FVC ≤ 50% vs the 13 with FVC > 50% predicted. No significant difference in the changes in PA mean pressure (FVC ≤ 50%, −2 ± 8.1 mm Hg; FVC > 50%, −6 ± 4.9 mm Hg; P > .05), PVR (FVC ≤ 50%, −1.5 ± 2.59 Wood units; FVC > 50%, −1.9 ± 2.99 Wood units; P > .05), or 6MWD (FVC ≤ 50%, −24 ± 70.3 m; FVC > 50%, −23 ± 71.8 m; P > .05) were found between the two groups.

The effect of therapy on various health-related quality-of-life instruments are summarized in Table 4. After 16 weeks of therapy, there was no significant change between baseline and week 16 for either the placebo or the bosentan arms on the at-rest Borg score for dyspnea, fatigue assessment score, and Short Form-36 total, physical component, and mental component scores. Similarly, there was no change in St. George’s Respiratory Questionnaire total, symptoms, activity, and impact scores. Additionally, no change was seen in the WHO classification for either treatment group (data not shown).

Table Graphic Jump Location
Table 4 —Effect of Therapy on Quality of Life

Data are presented as mean ± SD.

During the 16 weeks of the study, there were no deaths. One patient had an above-knee amputation. This patient was treated with placebo and had previously known peripheral vascular disease. Monthly liver function testing showed no abnormalities that required dose modification.

Based on case reports and series,12,15,21 we studied the effectiveness of bosentan in the treatment of SAPH. We found that 16 weeks of bosentan treatment was associated with a significant improvement in pulmonary hemodynamics as measured by both PA mean pressure and PVR. No improvement in pulmonary hemodynamics was found in the placebo group. The change in PA mean pressure was significantly different between the groups, and no significant changes in functional class, quality of life, or 6MWD were seen. We excluded patients with severe pulmonary hypertension, including those with NYHA functional class IV or a cardiac index of < 2 L/min/m2. We also excluded patients with an elevated PAOP to avoid studying those with left ventricular dysfunction due to pulmonary hypertension.

Several studies have demonstrated that 12 to 16 weeks of bosentan therapy can cause a significant improvement in some pulmonary hemodynamic parameters in patients with pulmonary hypertension,1,22,23 congenital heart disease, Eisenmenger syndrome,24 and chronic thrombotic emboli.25 In these studies, the difference in PVR between the bosentan and placebo groups was around 20% to 30%, similar to what was found in the current study. Treatment with bosentan was associated with an average decrease in PA mean pressure of around 5 mm Hg, similar to that found in the current study. Prior studies of sildenafil12,13 and iloprost10 demonstrated improvement in pulmonary hypertension in some of these patients; however, these studies did not include a placebo group. Additionally, two of these studies were retrospective and evaluated patients after a variable treatment period.12,13

In comparing the change in pulmonary hemodynamics with 6MWD, some studies demonstrated a significant improvement in 6MWD in other conditions with pulmonary hypertension.24,26 However, not all studies demonstrated a significant improvement in pulmonary hemodynamics associated with a significant improvement in 6MWD.23,25 In the current study, we were unable to demonstrate a significant improvement in 6MWD after 16 weeks of therapy, which could be a result of a relatively small sample size, a short time of treatment, superimposed acute events causing worsening of the sarcoidosis,27 or the presence of pulmonary fibrosis in one-half of the patients. For SAPH, two previous studies with either sildenafil13 or inhaled iloprost10 found some patients with significant improvement of pulmonary hemodynamics without a significant change in 6MWD. In a study of various treatments for SAPH, Barnett et al12 showed significant improvement in both pulmonary hemodynamics and 6MWD. The repeat 6MWT was done on average 14 months after initiation of therapy. Significant improvement in 6MWD was more likely to occur in patients with an FVC > 50%. In the current study, we analyzed patients with an FVC > 50% and could not demonstrate a significant improvement in 6MWD after 16 weeks of therapy. A previous study of ambrisentan did not show improvement in 6MWD after 24 weeks of therapy, but no pulmonary hemodynamics were measured after treatment.11

The cause of pulmonary hypertension in sarcoidosis is multifactorial, including a direct vascular effect and as a result of pulmonary fibrosis.28 This mixed pattern could potentially lead to different responses to treatment, depending on the cause of the pulmonary hypertension.12 This may also affect the change in the 6MWD. In the current study, one-half of the patients had evidence of pulmonary fibrosis on chest radiograph, an FVC < 60%, or both. Although there is some suggestion that bosentan may help to improve lung function in some patients with pulmonary fibrosis,29 a subsequent larger study failed to demonstrate improvement after 1 year of bosentan therapy compared with placebo in patients with idiopathic pulmonary fibrosis.30

Bosentan therapy has been shown to lead to significant oxygen desaturation in patients with severe COPD.31 In that study, bosentan treatment was not associated with improvement in pulmonary hemodynamics as assessed by echocardiography. In hypoxic conditions, treatment with bosentan has been shown to improve both pulmonary hemodynamics and oxygen saturation.32,33 In the current study, several patients required supplemental oxygen at rest, and more experienced significant desaturation with exercise. This has been seen in other studies of SAPH.7 After 16 weeks of therapy in the current study, patients in both groups were receiving more supplemental oxygen at rest and with exercise; however, there was no significant difference between groups. Two patients (9%) treated with bosentan required an increase in supplemental oxygen by > 2 L/min, but no patients in the placebo group required an increase. In patients with advanced idiopathic pulmonary fibrosis, treatment with sildenafil was not associated with worsening of oxygenation compared with placebo.34 However, we would recommend that all patients with SAPH be monitored for worsening hypoxia, especially with exercise.

Previous open-label trials of ambrisentan11 and iloprost10 demonstrated improvement in the St. George’s Respiratory Questionnaire score after 16 to 24 weeks of therapy. In the current study, we did not observe a change for either the active or the placebo treatment groups. In general, measurement of quality of life during treatment has led to mixed results in pulmonary hypertension,35 particularly in relatively short studies, such as the current one. It is possible that a more-prolonged treatment will lead to significant changes in health-related quality of life. The treatment of SAPH may also be useful as a bridge to lung transplantation.13 Although there are several potential treatments for SAPH, the current study is the first, to our knowledge, to demonstrate improvement compared with placebo. We also found no major toxicities associated with the use of bosentan in patients with SAPH. It has been previously demonstrated that in patients with advanced pulmonary sarcoidosis, the presence of pulmonary hypertension is associated with increased mortality.6,36 Whether treating SAPH will improve survival remains to be proven.

In conclusion, we found that 16 weeks of bosentan therapy in patients with SAPH is associated with a significant improvement in PA mean pressure and PVR. The level of improvement was similar to that reported in other WHO groups treated with bosentan. The treatment was well tolerated. The effect of treatment over longer periods will require further investigation.

Author contributions: Dr Baughman had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Baughman: contributed to the study design and execution, patient recruitment, and review of the final manuscript.

Dr Culver: contributed to the study design and execution, patient recruitment, and review of the final manuscript.

Dr Cordova: contributed to the study design and execution, patient recruitment, and review of the final manuscript.

Dr Padilla: contributed to the study design and execution, patient recruitment, and review of the final manuscript.

Dr Gibson: contributed to the study design and execution, patient recruitment, and review of the final manuscript.

Dr Lower: contributed to the study design and execution, patient recruitment, and review of the final manuscript.

Dr Engel: contributed to the study design and execution, patient recruitment, and review of the final manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Drs Baughman, Culver, Cordova, Padilla, Gibson, Lower, and Engel’s institutions received support from Actelion Pharmaceuticals US, Inc, to complete this study. Dr Engel has received grant monies and serves as a consultant for Actelion Pharmaceuticals US, Inc.

Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

6MWD

6-min walk distance

6MWT

6-min walk test

NYHA

New York Heart Association

PA

pulmonary artery

PAOP

pulmonary artery occlusion pressure

PVR

pulmonary vascular resistance

SAPH

sarcoidosis-associated pulmonary hypertension

WHO

World Health Organization

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King TE Jr, Brown KK, Raghu G, et al. BUILD-3: a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;184(1):92-99. [CrossRef]
 
Stolz D, Rasch H, Linka A, et al. A randomised, controlled trial of bosentan in severe COPD. Eur Respir J. 2008;32(3):619-628. [CrossRef]
 
Modesti PA, Vanni S, Morabito M, et al. Role of endothelin-1 in exposure to high altitude: Acute Mountain Sickness and Endothelin-1 (ACME-1) study. Circulation. 2006;114(13):1410-1416. [CrossRef]
 
Faoro V, Boldingh S, Moreels M, et al. Bosentan decreases pulmonary vascular resistance and improves exercise capacity in acute hypoxia. Chest. 2009;135(5):1215-1222. [CrossRef]
 
Zisman DA, Schwarz M, Anstrom KJ, Collard HR, Flaherty KR, Hunninghake GW; Idiopathic Pulmonary Fibrosis Clinical Research Network. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med. 2010;363(7):620-628. [CrossRef]
 
Chen H, Taichman DB, Doyle RL. Health-related quality of life and patient-reported outcomes in pulmonary arterial hypertension. Proc Am Thorac Soc. 2008;5(5):623-630. [CrossRef]
 
Nardi A, Brillet PY, Letoumelin P, et al. Stage IV sarcoidosis: comparison of survival with the general population and causes of death. Eur Respir J. 2011;38(6):1368-1373. [CrossRef]
 

Figures

Figure Jump LinkFigure 1. Flow chart demonstrating the outcome of all 43 patients who consented to participate in the clinical trial.19 Thirty-nine patients were randomized to receive either bosentan or placebo. Four patients stopped the study drug before week 8. Five patients did not undergo repeat RHC. One patient in the placebo group had repeat RHC but was unable to repeat the 6MWT because of an above-knee amputation before week 16. 6MWT = 6-min walk test; pts = patients; RHC = right-sided heart catheterization.Grahic Jump Location
Figure Jump LinkFigure 2. A, PA mean before and after 16 wk of bosentan therapy. There was a significant fall in PA mean pressure (−4 ± 6.6 mm Hg, P < .02). B, PA mean before and after 16 wk of placebo therapy. There was no significant change in PA mean pressure (1 ± 3.7 mm Hg, P > .05). PA = pulmonary artery.Grahic Jump Location
Figure Jump LinkFigure 3. A, PVR before and after 16 wk of bosentan therapy. There was a significant fall in PVR (−1.7 ± 2.75 Wood units, P < .02). B, PVR before and after 16 wk of placebo therapy. There was no change in PVR (0.1 ± 1.42 Wood units, P > .05). PVR = pulmonary vascular resistance.Grahic Jump Location
Figure Jump LinkFigure 4. Change in 6MWD after 16 wk of either bosentan or placebo therapy. There was no significant difference between the two treatment groups. 6MWD = 6-min walk distance.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Clinical Features of Study Patients

Data are presented as mean ± SD or counts. 6MWD = 6-min walk distance; NYHA = New York Heart Association.

a 

Eighteen patients in the bosentan group and nine patients in the placebo group used prednisone.

b 

Patients could be receiving more than one therapy.

c 

Includes one patient not taking prednisone or receiving other therapy.

Table Graphic Jump Location
Table 2 —Hemodynamic Values From Right-Sided Heart Catheterization Initially and After 16 Wk of Therapy

Data are presented as mean ± SD. PA = pulmonary artery; PAOP = pulmonary artery occlusion pressure; PVR = pulmonary vascular resistance.

a 

Differs from baseline, P < .05.

b 

Differs from bosentan group, P < .05.

c 

Differs from baseline, P < .02.

d 

Differs from baseline, P < .02.

Table Graphic Jump Location
Table 3 —Rate of Desaturation During 6MWT

Data are presented as No. positive/total No. (%). Oxygen desaturation defined as either a > 5% decrease in lowest oxygen saturation compared with rest, increase in oxygen supplementation of > 2 L/min, or both. 6MWT = 6-min walk test.

a 

One patient was unable to do the 6MWT at week 16 because of above-knee amputation.

Table Graphic Jump Location
Table 4 —Effect of Therapy on Quality of Life

Data are presented as mean ± SD.

References

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King TE Jr, Brown KK, Raghu G, et al. BUILD-3: a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;184(1):92-99. [CrossRef]
 
Stolz D, Rasch H, Linka A, et al. A randomised, controlled trial of bosentan in severe COPD. Eur Respir J. 2008;32(3):619-628. [CrossRef]
 
Modesti PA, Vanni S, Morabito M, et al. Role of endothelin-1 in exposure to high altitude: Acute Mountain Sickness and Endothelin-1 (ACME-1) study. Circulation. 2006;114(13):1410-1416. [CrossRef]
 
Faoro V, Boldingh S, Moreels M, et al. Bosentan decreases pulmonary vascular resistance and improves exercise capacity in acute hypoxia. Chest. 2009;135(5):1215-1222. [CrossRef]
 
Zisman DA, Schwarz M, Anstrom KJ, Collard HR, Flaherty KR, Hunninghake GW; Idiopathic Pulmonary Fibrosis Clinical Research Network. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med. 2010;363(7):620-628. [CrossRef]
 
Chen H, Taichman DB, Doyle RL. Health-related quality of life and patient-reported outcomes in pulmonary arterial hypertension. Proc Am Thorac Soc. 2008;5(5):623-630. [CrossRef]
 
Nardi A, Brillet PY, Letoumelin P, et al. Stage IV sarcoidosis: comparison of survival with the general population and causes of death. Eur Respir J. 2011;38(6):1368-1373. [CrossRef]
 
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