Randomised controlled trials (RCTs) with pulmonary arterial hypertension (PAH)-targeted therapy in lung disease
| First author (year) [ref.] | Subjects n | Inclusion criteria | Study design | Diagnosis of PH | Baseline haemodynamics# | Baseline PFTs# | Therapy | Duration | Primary end-point result | Other outcomes |
| COPD | ||||||||||
| Vonbank (2003) [86] | 40 | COPD on supplemental oxygen with PH by RHC | RCT (open label) | RHC: mPAP ≥25 mmHg | mPAP 27.6±4.4 mmHg, CI 2.7±0.6 L·min−1·m−2 | FEV1 1.09±0.4 L, FEV1/FVC 44.5% | “Pulsed” nitric oxide with oxygen vs oxygen | 3 months | PVRI, improved | Improved mPAP, CO and PVR; no worsened hypoxaemia |
| Stolz (2008) [53] | 30 | GOLD III–IV; no haemodynamic requirement | RCT (2:1) | Echo | sPAP 32 (29–38) mmHg | Not reported | Bosentan 125 mg 2 times daily | 12 weeks | 6MWD, no change | Worsened hypoxaemia and health-related QoL |
| Valerio (2009) [50] | 32 | COPD with PH by RHC | RCT (open label) | RHC | mPAP 37±5 mmHg | FEV1 37±18% | Bosentan 125 mg 2 times daily | 18 months | No defined primary | mPAP, PVR, BODE index and 6MWD improved |
| Rao (2011) [87] | 33 | GOLD III–IV | RCT | Echo: sPAP >40 mmHg | sPAP 52.7±11.9 mmHg | FEV1 32.5±11.1% | Sildenafil 20 mg 3 times daily | 12 weeks | 6MWD, increased 190 m | Decrease in sPAP |
| Blanco (2013) [88] | 60 | COPD with PH by RHC or echo | RCT | RHC: mPAP ≥25 mmHg; echo: sPAP ≥35 mmHg | sPAP 42±10 mmHg, mPAP 31±5 mmHg | FEV1 32±11% | Sildenafil 20 mg or placebo 3 times daily and PR | 3 months | Exercise endurance time, no change | No change in 6MWD, peak V′O2, QoL or oxygenation |
| Goudie (2014) [89] | 120 | COPD with PH by echo | RCT | Echo: pulmonary acceleration time <120 ms or sPAP >30 mmHg | Echo: sPAP 42±10 mmHg | FEV1 41±16% | Tadalafil 10 mg daily | 12 weeks | 6MWD, no change | Decreased sPAP compared with placebo; no difference in QoL, BNP or SaO2 |
| Vitulo (2016) [49] | 28 | COPD with PH by RHC | RCT (2:1) | RHC: mPAP >35 mmHg (if FEV1 <30%), mPAP ≥30 mmHg (if FEV1 ≥30%) | mPAP 39±8 mmHg, CI 2.4±0.5 L·min−1·m−2, PVR 7±2.6 WU | FEV1 54±22%, DLCO 33±12% | Sildenafil 20 mg 3 times daily | 16 weeks | PVR, decreased 1.4 WU | Improved CI, BODE scores and QoL; no effect on gas exchange |
| ILD | ||||||||||
| Han (2013) [90] | 119 | IPF with echo available (66% of the whole cohort) | RCT | Echo: RVSD | Not available | FVC 57%, DLCO 26% | Sildenafil 20 mg 3 times daily | 12 weeks | 6MWD, less decline in patients with RVSD on sildenafil | Improvement in QoL in patients with RVSD |
| Corte (2014) [60] | 60 | IPF or idiopathic fibrotic NSIP | RCT (2:1) | RHC: mPAP ≥25 mmHg | mPAP 37±9.9 mmHg, CI 2.2±0.5 L·min−1·m−2 | FVC 55.7±20%, KCO 45±22% | Bosentan | 16 weeks | PVRI decrease of 20%, negative | Secondary end-points all negative; no change in functional capacity or symptoms |
| Raghu (2015) [14]¶ | 68 | IPF with group 2 PH (14% of whole cohort) | RCT (2:1) | RHC | mPAP 30±8 mmHg | FVC 67±12%, DLCO 39±15% | Ambrisentan 10 mg·day−1 | Event-driven study terminated early | Disease progression, unfavourable trend | More hospitalised ambrisentan arm |
| Nathan (2017) [57] | 147 | IIP, FVC >45%, mPAP >25 mmHg | RCT | RHC | mPAP 33.2±8.2 mmHg, CI 2.6±0.7 L·min−1·m−2 | FVC 76.3±19%, DLCO 32±12% | Riociguat 2.5 mg 3 times daily | 26 weeks | 6MWD, no difference at study halt | Study stopped early for increased harm to riociguat arm (death and hospitalisation) |
| Sarcoidosis | ||||||||||
| Barnett (2009) [65] | 22 | Any SAPH and treatment with PAH therapy | Retrospective case series | RHC | mPAP 46.1±2.7 mmHg, CO 4.2±0.4 L·min−1 | FVC 53.6±3.3%, FEV1 51.2±3.7% | Bosentan, sildenafil | Median (range) 11 (5.2–46.6) months | 6MWD improved by 59 m | NYHA FC improvement in nine patients |
| Baughman (2009) [66] | 22 | Any SAPH | Prospective open label | RHC | mPAP 33 (20–62) mmHg, CO 5.9 (3.1–9.5) L·min−1, PVR 5.1 (1.96–16.3) WU | FVC 50% (41–101%), FEV1/FVC 73% (53–91%) | Inhaled iloprost | 4 months | 6MWD unchanged 0.6±40 m | 7 patients withdrew; 6 patients with ≥20% decrease in PVR and 3 patients with ≥30 m increase in 6MWD |
| Judson (2011) [91] | 25 | mPAP >25 mmHg, PVR >3 WU, FVC >40%, WHO FC II or III, 6MWD 150–450 m | Prospective open label | RHC | mPAP 32.7±7 mmHg, CO 4.45±0.94 L·min−1·m−2, PVR 5.86±2.3 WU | FEV1 59±21%, FVC 61.5±16.5% | Ambrisentan 10 mg daily | 24 weeks | No change in 6MWD 9.8±55 m | 11 patients discontinued drug at 12 weeks; 10 out of 21 patients who completed had improvements in WHO FC and QoL |
| Baughman (2014) [67] | 39 | mPAP ≥25 mmHg, NYHA FC II or III | RCT (2:1) | RHC | mPAP 36±7 mmHg, CI 2.6±0.7 L·min−1·m−2 | FVC 60±16.6% | Bosentan | 16 weeks | Decrease in mPAP (to 32 mmHg) | No change in 6MWD; PVR decreased from 6.1 to 4.4 WU |
| Keir (2014) [92] | 33 | Any SAPH | Retrospective case series | RHC | mPAP 44±8.6 mmHg, PVR 10±5.1 WU, CI 2.1±0.6 L·min−1·m−2, TAPSE 17.5 (8–27) mm | FEV1 51.8±18.3%, FVC 64.8±22.3% | Sildenafil n=29, bosentan n=4 | 6 months | None identified | 6MWD improved 14 m; BNP and TAPSE improved |
| Bonham (2015) [93] | 26 | Any treated SAPH, no left-sided disease | Retrospective case series | RHC | mPAP 46 (38–56) mmHg, CI 2.1 (1.8–2.6) L·min−1·m−2, PVR 8.3 (5.7–11.1) WU | FEV1 48% (38–59%), FVC 48% (44–64%), DLCO 29% (25–44%) | Epoprostenol n=7, treprostinil n=6, ERA n=12, PDE5i n=20 | Variable | None identified | Increased CI/CO, decreased PVR (median 12.7 months in 10 prostacyclin patients) and improved N-terminal pro-BNP |
PH: pulmonary hypertension; PFT: pulmonary function test; COPD: chronic obstructive pulmonary disease; RHC: right heart catheterisation; mPAP: mean pulmonary arterial pressure; CI: cardiac index; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; PVR(I): pulmonary vascular resistance (index); CO: cardiac output; GOLD: Global Initiative for Chronic Obstructive Lung Disease; sPAP: systolic PAP; 6MWD: 6-min walk distance; QoL: quality of life; BODE: body mass, airflow obstruction, dyspnoea, exercise capacity; echo: echocardiography; PR: pulmonary rehabilitation; V′O2: oxygen uptake; BNP: brain natriuretic peptide; SaO2: arterial oxygen saturation; WU: Wood Units; DLCO: diffusing capacity of the lung for carbon monoxide; ILD: interstitial lung disease; IPF: idiopathic pulmonary fibrosis; RVSD: right ventricular systolic dysfunction; NSIP: non-specific interstitial pneumonia; KCO: transfer coefficient of the lung for carbon monoxide; IIP: idiopathic interstitial pneumonia; SAPH: sarcoidosis-associated PH; NYHA: New York Heart Association; FC: Functional Class; WHO: World Health Organization; TAPSE: tricuspid annular plane systolic excursion; ERA: endothelin receptor antagonist; PDE5i: phosphodiesterase type 5 inhibitor. #: for RCTs, the data for the treatment arm are reported as mean±sd or median (interquartile range); ¶: subgroup analysis of the ARTEMIS-IPF trial (study performed to evaluate the antifibrotic effects of the study medication, not all patients had PH).