Randomised controlled trials (RCTs) with pulmonary arterial hypertension (PAH)-targeted therapy in lung disease

First author (year) [ref.]Subjects nInclusion criteriaStudy designDiagnosis of PHBaseline haemodynamics#Baseline PFTs#TherapyDurationPrimary end-point resultOther outcomes
 Vonbank (2003) [86]40COPD on supplemental oxygen with PH by RHCRCT (open label)RHC: mPAP ≥25 mmHgmPAP 27.6±4.4 mmHg, CI 2.7±0.6 L·min−1·m−2FEV1 1.09±0.4 L, FEV1/FVC 44.5%“Pulsed” nitric oxide with oxygen vs oxygen3 monthsPVRI, improvedImproved mPAP, CO and PVR; no worsened hypoxaemia
 Stolz (2008) [53]30GOLD III–IV; no haemodynamic requirementRCT (2:1)EchosPAP 32 (29–38) mmHgNot reportedBosentan 125 mg 2 times daily12 weeks6MWD, no changeWorsened hypoxaemia and health-related QoL
 Valerio (2009) [50]32COPD with PH by RHCRCT (open label)RHCmPAP 37±5 mmHgFEV1 37±18%Bosentan 125 mg 2 times daily18 monthsNo defined primarymPAP, PVR, BODE index and 6MWD improved
 Rao (2011) [87]33GOLD III–IVRCTEcho: sPAP >40 mmHgsPAP 52.7±11.9 mmHgFEV1 32.5±11.1%Sildenafil 20 mg 3 times daily12 weeks6MWD, increased 190 mDecrease in sPAP
 Blanco (2013) [88]60COPD with PH by RHC or echoRCTRHC: mPAP ≥25 mmHg; echo: sPAP ≥35 mmHgsPAP 42±10 mmHg, mPAP 31±5 mmHgFEV1 32±11%Sildenafil 20 mg or placebo 3 times daily and PR3 monthsExercise endurance time, no changeNo change in 6MWD, peak VO2, QoL or oxygenation
 Goudie (2014) [89]120COPD with PH by echoRCTEcho: pulmonary acceleration time <120 ms or sPAP >30 mmHgEcho: sPAP 42±10 mmHgFEV1 41±16%Tadalafil 10 mg daily12 weeks6MWD, no changeDecreased sPAP compared with placebo; no difference in QoL, BNP or SaO2
 Vitulo (2016) [49]28COPD with PH by RHCRCT (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 WUFEV1 54±22%, DLCO 33±12%Sildenafil 20 mg 3 times daily16 weeksPVR, decreased 1.4 WUImproved CI, BODE scores and QoL; no effect on gas exchange
 Han (2013) [90]119IPF with echo available (66% of the whole cohort)RCTEcho: RVSDNot availableFVC 57%, DLCO 26%Sildenafil 20 mg 3 times daily12 weeks6MWD, less decline in patients with RVSD on sildenafilImprovement in QoL in patients with RVSD
 Corte (2014) [60]60IPF or idiopathic fibrotic NSIPRCT (2:1)RHC: mPAP ≥25 mmHgmPAP 37±9.9 mmHg, CI 2.2±0.5 L·min−1·m−2FVC 55.7±20%, KCO 45±22%Bosentan16 weeksPVRI decrease of 20%, negativeSecondary end-points all negative; no change in functional capacity or symptoms
 Raghu (2015) [14]68IPF with group 2 PH (14% of whole cohort)RCT (2:1)RHCmPAP 30±8 mmHgFVC 67±12%, DLCO 39±15%Ambrisentan 10 mg·day−1Event-driven study terminated earlyDisease progression, unfavourable trendMore hospitalised ambrisentan arm
 Nathan (2017) [57]147IIP, FVC >45%, mPAP >25 mmHgRCTRHCmPAP 33.2±8.2 mmHg, CI 2.6±0.7 L·min−1·m−2FVC 76.3±19%, DLCO 32±12%Riociguat 2.5 mg 3 times daily26 weeks6MWD, no difference at study haltStudy stopped early for increased harm to riociguat arm (death and hospitalisation)
 Barnett (2009) [65]22Any SAPH and treatment with PAH therapyRetrospective case seriesRHCmPAP 46.1±2.7 mmHg, CO 4.2±0.4 L·min−1FVC 53.6±3.3%, FEV1 51.2±3.7%Bosentan, sildenafilMedian (range) 11 (5.2–46.6) months6MWD improved by 59 mNYHA FC improvement in nine patients
 Baughman (2009) [66]22Any SAPHProspective open labelRHCmPAP 33 (20–62) mmHg, CO 5.9 (3.1–9.5) L·min−1, PVR 5.1 (1.96–16.3) WUFVC 50% (41–101%), FEV1/FVC 73% (53–91%)Inhaled iloprost4 months6MWD unchanged 0.6±40 m7 patients withdrew; 6 patients with ≥20% decrease in PVR and 3 patients with ≥30 m increase in 6MWD
 Judson (2011) [91]25mPAP >25 mmHg, PVR >3 WU, FVC >40%, WHO FC II or III, 6MWD 150–450 mProspective open labelRHCmPAP 32.7±7 mmHg, CO 4.45±0.94 L·min−1·m−2, PVR 5.86±2.3 WUFEV1 59±21%, FVC 61.5±16.5%Ambrisentan 10 mg daily24 weeksNo change in 6MWD 9.8±55 m11 patients discontinued drug at 12 weeks; 10 out of 21 patients who completed had improvements in WHO FC and QoL
 Baughman (2014) [67]39mPAP ≥25 mmHg, NYHA FC II or IIIRCT (2:1)RHCmPAP 36±7 mmHg, CI 2.6±0.7 L·min−1·m−2FVC 60±16.6%Bosentan16 weeksDecrease in mPAP (to 32 mmHg)No change in 6MWD; PVR decreased from 6.1 to 4.4 WU
 Keir (2014) [92]33Any SAPHRetrospective case seriesRHCmPAP 44±8.6 mmHg, PVR 10±5.1 WU, CI 2.1±0.6 L·min−1·m−2, TAPSE 17.5 (8–27) mmFEV1 51.8±18.3%, FVC 64.8±22.3%Sildenafil n=29, bosentan n=46 monthsNone identified6MWD improved 14 m; BNP and TAPSE improved
 Bonham (2015) [93]26Any treated SAPH, no left-sided diseaseRetrospective case seriesRHCmPAP 46 (38–56) mmHg, CI 2.1 (1.8–2.6) L·min−1·m−2, PVR 8.3 (5.7–11.1) WUFEV1 48% (38–59%), FVC 48% (44–64%), DLCO 29% (25–44%)Epoprostenol n=7, treprostinil n=6, ERA n=12, PDE5i n=20VariableNone identifiedIncreased 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; VO2: 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).