Key randomised controlled trials of pulmonary hypertension (PH) therapies in interstitial lung disease (ILD) and COPD
| Author/study | Year | N | Drug | Lung disease | FEV1 (%) | FVC (%) | DLCO (%) | 6MWD (m) | Key inclusion criteria | Study enriched for PH? | PH severity | Primary endpoint | Findings |
| ILD | |||||||||||||
| King et al. [13] (BUILD-3) | 2011 | 406 | Bosentan | IPF | NS | 75 | 48 | NS | CT: <5% honeycombing DLCO >30% | No | NS | Disease progression including FVC and DLCO | No effect on primary or secondary endpoints |
| Raghu et al. [14] (ARTEMIS-IPF) | 2013 | 329 | Ambrisentan | IPF | NS | 69 | 42 | 410 | CT: <5% honeycombing DLCO: NS | No | mPAP 20±6 mmHg | Disease progression including FVC and DLCO | ↑Disease progression and hospitalisation ↓FVC |
| Raghu et al. [15] (MUSIC) | 2013 | 119 | Macitentan | IPF | NS | 77 | 47 | NS | CT: non-extensive honeycombing DLCO: NS | No | NS | Δ FVC | No effect on primary or secondary endpoints |
| Corte et al. [16] (BPHIT) | 2014 | 40 | Bosentan | IPF or fibrotic idiopathic NSIP | 59 | 56 | 21 | 149 | CT: NS DLCO: NS mPAP ≥25 mmHg PAWP ≤15 mmHg | Yes | mPAP 37±10 mmHg PVR 7.4±4 WU | Δ PVRi | No effect on primary or secondary endpoints |
| Han et al. [17] (STEP-IPF sub-study) | 2013 | 56 | Sildenafil | IPF | NS | 57 | 26 | 273 | CT: ILD > emphysema Available echo DLCO ≤35% | Yes | RVSP 43±16 mmHg# | Δ 6MWD | 6MWD stabilised and QoL improved in patients with ↓RV function |
| Kolb et al. [18] (INSTAGE) and sub-study [20] | 2018 | 137 | Sildenafil on background of ninetdanib | IPF: 37% co-existing emphysema | NS | 68 | 26 | NS | CT: NS DLCO ≤35% | Yes | Echo signs of right heart dysfunction in 45% of patients receiving sildenafil | Δ SGRQ | No effect on primary endpoint Beneficial effects on BNP in patients with RV dysfunction |
| Behr et al. [19] | 2021 | 88 | Sildenafil on background of pirfenidone | IPF | 70 | NS | 26 | 318 | CT: NS DLCO ≤40% mPAP >20mmHg and PAWP ≤15 or intermediate/high risk of PH at echo | Yes | mPAP 27±7 mmHg¶ sPAP 56±20 mmHg+ | Disease progression including 6MWD | No effect on primary endpoint |
| Nathan et al. [21] (RISE-IIP) | 2019 | 147 | Riociguat | IIP (74% IPF) | 76 | 76 | 32 | 307 | CT: NS FVC ≥45% mPAP ≥25 mmHg | Yes | mPAP 33±8 mmHg PVR 4.9±2.6 WU | Δ 6MWD | No effect on primary endpoint Study terminated early due to ↑SAE including mortality in riociguat arm |
| Waxman et al. [22] (INCREASE) | 2021 | 163 | Inhaled treprostinil | ILD (23% IPF, 13% idiopathic NSIP, 26% CFES, 25% CTD, 6% HSP) | 64 | 63 | 30 | 254 | CT: NS Group 3 PH mPAP ≥25 mmHg PAWP ≤15 mmHg PVR >3 WU FVC <70% in CTD | Yes | mPAP 37 (25–74) mmHg§ PVR 6.4 (3–18) WU§ NT-proBNP 1857 pg·mL−1 | Δ 6MWD | Placebo-controlled ↑6MWD 31m ↓NT-proBNP ↓Clinical worsening Subgroup analysis: treprostinil better if PVR ≥4 WU but not <4 WU, and if DLCO <40% but not ≥40%; benefit seen in IIP and CTD, but not in CFES |
| COPD | |||||||||||||
| Stolz et al. [23] | 2008 | 20 | Bosentan | COPD and/or emphysema | NS | NS | NS | 339 | GOLD III–IV | No | RVSP 32 (29–38) mmHgƒ | Δ 6MWD | No effect on primary endpoint PaO2 and QoL worsened |
| Blanco et al. [24] | 2013 | 29 | Sildenafil | COPD | 33 | 67 | NS | 392 | COPD and evidence of PH (TRV >2.7 m·s−1 or mPAP ≥25 mmHg) | Yes | TRV 3.1±0.3 mmHg mPAP 32±6 mmHg## | Δ Cycle endurance time | No effect on primary or secondary endpoints |
| Goudie et al. [25] | 2014 | 60 | Tadalafil | COPD | 41 | NS | NS | 354 | COPD and evidence of PH (RVSP >30 mmHg or PAT <120 m·s−1) | Yes | RVSP 42±9 mmHg PAT 98±10 m·s−1 | Δ 6MWD | No effect on primary or secondary endpoints |
| Vitulo et al. [26] (SPHERIC-1) | 2017 | 18 | Sildenafil | COPD | 54 | NS | 33 | 229 | COPD and mPAP ≥35 mmHg if FEV1 <30% or mPAP ≥30 mmHg if FEV1 >30% | Yes | mPAP 39±13 mmHg PVR 7±2.6 WU | Δ PVR | ↓PVR Improved QoL ↑DLCO |
Haemodynamic data expressed as mean±sd, unless otherwise stated. #: measured in 63%; ¶: available in 18%; +: available in 92%; §: mean (range); ƒ: median (interquartile range); ##: measured in nine patients. N: number of patients receiving study drug; NS: not specified; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; DLCO: diffusing capacity of the lung for carbon monoxide; 6MWD: 6-min walking distance; IPF: idiopathic pulmonary fibrosis; NSIP: non-specific interstitial pneumonia; IIP: idiopathic interstitial pneumonia; CFES: combined fibrosis and emphysema syndrome; CTD: connective tissue disease; HSP: hypersensitivity pneumonitis; CT: computed tomography; mPAP: mean pulmonary arterial hypertension measured at right heart catheterisation; PAWP: pulmonary arterial wedge pressure; PVR: pulmonary vascular resistance; GOLD: Global Initiative for Chronic Obstructive Lung Disease; RVSP: right ventricular systolic pressure measured at echocardiography; PAT: pulmonary arterial acceleration time; sPAP: systolic pulmonary arterial pressure measured at echocardiography; NT-proBNP: N-terminal-pro-B-type-natriuretic peptide; TRV: tricuspid regurgitant jet velocity; PVRi: PVR indexed for body surface area; SGRQ: St George's Respiratory Questionnaire; QoL: quality of life; RV: right ventricular; SAE: serious adverse event; PaO2: arterial oxygen tension.