Figures
- Fig. 1—
Flow diagram showing the trial design. COPD: chronic obstructive pulmonary disease; MRSA: methicillin-resistant Staphylococcus aureus.
- Fig. 2—
Individual patient data showing the 6-min walking distance at baseline and at 12 weeks in patients assigned a) placebo (n = 10) and b) bosentan (n = 20). The changes in the 6-min walking distance were similar across both treatment groups (p = 0.474). The mean±sd distance walked in 6 min decreased by 10 m in patients assigned bosentan (from 339±81 m at baseline to 329±94 m at week 12, p = 0.040), and remained unchanged in those given placebo (331±116 m at baseline and 331±123 m at week 12, p = 0.100).
- Fig. 3—
Alveolar–arterial gradient at baseline, 4 weeks and 12 weeks in patients assigned bosentan (□) and placebo (▓). The alveolar–arterial gradient increased significantly in patients assigned bosentan compared with those assigned placebo (p = 0.029). In the bosentan group, median (interquartile range) alveolar–arterial gradient was 31.4 (28.1–37.1), 42.0 (37.4–44.5) and 40.4 (31.5–44.9) mmHg at baseline, 4 weeks and 12 weeks, respectively. The corresponding values for the placebo group were 33.4 (32.5–48.2), 34.4 (29.3–41.3), and 34.3 (20.9–42.8) mmHg, respectively.
- Fig. 4—
a) Transversal thoracic-computed tomography (CT) scan showing emphysematous changes in the right anterior upper lobe. b) Transversal fusion image combining a thoracic CT scan and perfusion signal. Colour-coded areas denote perfusion of lung parenchyma (yellow: high-perfusion areas; blue: low-perfusion areas; red: intermediate perfusion; black: no perfusion).
- Fig. 5—
Transversal, coronal and sagital thoracic computed tomography (CT) scans showing a–c) the pulmonary morphology, d–f) the perfusion signal showing the perfusion difference between baseline and 12 weeks (blue: decreased perfusion at 12 weeks compared with baseline; red: increased perfusion at 12 weeks compared with baseline), and g–i) fusion thoracic CT and perfusion signal images combining morphology and perfusion.
Tables
- Table 1—
Demographic and haemodynamic characteristics at baseline
Placebo Bosentan p-value Subjects n 10 20 Demographic variables Age yrs 65±7.9 69.5±8.8 0.184 Male 7 (70) 11 (55) 0.694 Weight kg 76.9±16.4 66.3±14.0 0.075 Height cm 165±6.1 166.9±6.9 0.464 Body mass index 28.1±4.7 24.0±5.9 0.064 Pack-yrs 80±38 38±21 0.001 Ex-smoker 8 (80) 18 (90) 0.584 Current smoker 2 (20) 2 (10) 0.584 Symptoms Dizziness 4 (40) 4 (20) 0.384 Peripheral oedema 2 (20) 5 (25) 1 Physical examination Wheezing 2 (20) 8 (40) 0.420 Rales 1 (10) 1 (5) 1 GOLD stages III# 6 (60) 11 (55) 1 IV¶ 4 (40) 9 (45) Exercise tolerance 6-min walking distance m 331±116 339±81 0.817 Borg dyspnoea index levels 5.3±2.4 5.1±2.1 0.084 Regular medication use Long-term oxygen therapy 3 (30) 8 (40) 0.702 Chronic diuretic use 3 (30) 5 (25) 1 Short-acting β2-agonists 10 (100) 20 (100) 1 Long-acting β2-agonists 10 (100) 20 (100) 1 Long-acting-anticholinergics 10 (100) 20 (100) 1 Inhaled steroids 10 (100) 20 (100) 1 Vital signs Respiratory frequency breaths·min−1 18±3 20±5 0.291 Peripheral O2 saturation % 92 (4) 93 (4) 0.510 fC beats·min−1 90±12 88±15 0.759 Systolic blood pressure mmHg 142±19 129±16 0.069 Diastolic blood pressure mmHg 87±7 78±9 0.009 Echocardiography Pulmonary hypertension at rest ≥30 mmHg+ 6 (60) 14 (70) 0.584 Median estimated systolic Ppa at rest mmHg+ 37 (20–42) 32 (29–38) 0.779 Left ventricular ejection fraction % 57±9 61±10 0.321 Data are presented as mean±sd, n (%) or median (interquartile range), unless otherwises stated. GOLD: Global Initiative for Chronic Obstructive Lung Disease; fC: cardiac frequency; Ppa: pulmonary arterial pressue. #: 30% predicted less than forced expiratory volume in one second ≤50% pred; ¶: forced expiratory volume in one second ≤30% pred; +: estimated pulmonary pressures without adding central venous pressure.
- Table 2—
Lung function testing and cardiopulmonary exercise test parameters
Placebo Bosentan p-value Baseline 12 weeks Baseline 12 weeks Subjects n 10 9 20 17 Body plethysmography Total lung capacity post-BD L 6.89±0.91 6.70±1.08 7.23±1.45 7.32±1.30 0.372 Total lung capacity post-BD % 120±22 114±14 126±15 124±14 0.927 Residual volume post-BD L 3.80±1.07 3.46±0.69 4.18±1.11 4.40±0.97 0.095 Residual volume post-BD % 174±68 151±28 184±51 188±38 0.094 FEV1 post-BD L 1.05±0.39 1.07±0.38 0.92±0.27 0.86±0.26 0.379 FEV1 post-BD % 41±14 42±14 38 ±13 35±12 0.482 FEV1/VC post-BD % 35±8 35±11 32±10 31±9 0.320 Diffusion capacity % 44±13 42±13 37±18 35±18 0.842 Cardiopulmonary exercise testing Respiratory quotient rest 0.86±0.07 0.89±0.11 0.85±0.11 0.85±0.07 0.282 Respiratory quotient max 0.88±0.04 0.86±0.06 0.85±0.07 0.80±0.06 0.056 fC rest beats·min−1 85±13.3 87±16 91.9±15 91±11 0.474 fC max beats·min−1 115±20 115±14 108±21 114±21 0.626 fC max % 75±13 75±8 72±15 76±15 0.489 O2 pulse at rest mL·beat−1 3.81±1.60 3.27±1.68 3.07±0.77 3.41±1.38 0.088 O2 pulse max mL·beat−1 9.02±2.91 9.98±3.11 8.69±4.56 7.90±3.02 0.156 O2 pulse max % 75±15 75±18 93±52 82±31 0.293 Minute ventilation rest L 13.6±3.6 13.8±5.0 14.0±2.8 15.4±4.8 0.498 Minute ventilation max L 34.6±10.7 36.0±12.2 31.4±9.1 30.3±7.2 0.114 Minute ventilation max % 47±13 48±14 45±15 43±15 0.276 V′O2 at rest mL·min·kg−1 4.1±1.0 4.9±1.9 4.3±0.8 3.5±1.7 0.288 V′O2 max mL·min·kg−1 13.4±2.4 13.9±2.8 13.8±3.0 13.4±3.4 0.113 V′O2 max % 63±11 64±15 54±12 50±12 0.304 O2 saturation at rest % 92±4 93±2 93±3 91±4 0.035 O2 saturation at max % 77±17 84±5 83±6 79±13 0.842 Data are presented as mean±sd, unless otherwise stated. BD: bronchodilator; FEV1: forced expiratory volume in one second; VC: vital capacity; fC: cardiac frequency; V′O2: maximal oxygen uptake.
- Table 3—
Cardiopulmonary haemodynamics at baseline and after therapy
Placebo Bosentan p-value Baseline 12 weeks Baseline 12 weeks Subjects n 10 9 20 14 Cardiopulmonary haemodynamics Systolic Ppa mmHg# 37 (20–42) 33 (29–39) 32 (29–38) 30 (26–34) 0.288 RV fractional area change % 34.2±11.8 43.9±7.9 42.7±11.0 50.5±6.8 0.935 Tricuspid annular motion mm 24.4±2.7 22.5±2.4 21.0±4.5 22.7±3.6 0.059 Early diastolic velocity RV cm·s−1 0.44±0.09 0.40±0.08 0.44±0.11 0.41±0.12 0.512 Late diastolic velocity RV 0.46±0.12 0.46±0.09 0.44±0.13 0.39±0.07 0.338 Early diastolic/late diastolic velocity RV 1.00±0.30 0.88±0.15 0.99±0.23 1.07±0.33 0.142 Tissue doppler imaging Early diastolic velocity cm·s−1 0.08±0.03 0.08±0.03 0.08±0.04 0.09±0.03 0.346 Late diastolic velocity cm·s−1 0.14±0.05 0.15±0.02 0.14±0.05 0.15±0.05 0.890 Systolic velocity cm·s−1 0.12±0.04 0.12±0.02 0.12±0.03 0.12±0.03 0.961 Pulmonary vascular resistance (dyne×s)·cm5 145±28 182±23 158±30 154±45 0.006 Cardiac index L·min·m2 3.3±0.79 3.39±0.58 2.45±0.41 2.66±0.65 0.296 Data are presented as median (interquartile range) or mean±sd, unless otherwise stated. Ppa: pulmonary arterial pressure; RV: right ventricle #: estimated pulmonary pressures without adding central venous pressure.
- Table 4—
Health-related life quality as assessed by the Short-Form-36 Health Survey (SF-36) at baseline and after therapy
Placebo Bosentan p-value Baseline 12 weeks Baseline 12 weeks Subjects n 10 9 20 14 Physical functioning 43.3±28.1 55.6±20.1 27.5±15.3 23.2±19.9 0.067 Role limitations due to physical health 23.0±38.1 53.1±47.1 16.3±33.7 7.1±26.7 0.082 Body pain 70.8±32.6 80.8±29.2 78.3±28.0 70.2±31.7 0.413 General health perceptions 50.5±20.0 62.4±19.0 43.2±20.9 39.1±20.4 0.018 Vitality 47.8±20.0 50.0±25.2 36.4±19.3 34.6±18.5 0.571 Social functioning 70.0±36.4 89.1±15.6 58.1±32.0 57.1±28.5 0.230 Role limitations due to emotional problems 63.3±45.7 79.2±35.4 43.3±49.7 59.5±49.2 0.970 Mental health 76.0±19.2 87.1±13.5 66.6±15.0 64.9±17.0 0.023 Total physical health 47.4±23.2 61.1±21.5 38.5±14.8 34.9±18.3 0.032 Total mental health 61.6±23.4 68.9±21.4 50.6±20.7 51.1±20.8 0.263 Total SF-36 Score 56.2±21.3 66.9±19.6 46.1±17.6 44.5±18.7 0.039 Data are presented as mean±sd, unless otherwise stated.
