First author, year [reference] | Participants | PAH subgroup | Mean age years | Follow-up duration | WHO functional class | Interventional group treatment (upfront therapy) | Control group treatment | Outcome measures | Adverse events |
Badagliacca,# 2018 [6] | 165 | IPAH | 54 | 155±65 days | 3.2±0.4 | Group 1: prostanoids+ERAs or PDE5i Group 2: ERAs+PDE5i | Group 3: ERAs or PDE5i Group 4: prostanoids | PVR, mPAP, CI, RAP, 6MWD | NR |
Badagliacca, 2021 [7] | 181 | IPAH, CTD-PAH, CHD-PAH with closed shunt | 53 | 180 (144–363) days | I–II: 37 (20.4) III: 127 (70.2) IV: 17 (9.4) | Ambrisentan-tadalafil or ambrisentan-sildenafil or bosentan-tadalafil or bosentan-sildenafil or macitentan-tadalafil or macitentan-sildenafil | NA | PVR, mPAP, CI, RAP, 6MWD | NR |
Chin, 2021 [8] | 247 | PAH | 51.9 | 26 weeks | I–II: 50 (20.2) III–IV: 197 (79.8) | Macitentan-tadalafil-selexipag | Macitentan-tadalafil-placebo | PVR, mPAP, CI, RAP, SvO2, NT-proBNP, 6MWD | Headache, diarrhoea, nausea, pain in extremity, jaw pain, vomiting |
D'Alto, 2020 [9] | 21 | IPAH | 44 | 24±14 months | III: 12 (57) IV: 9 (43) | Ambrisentan-tadalafil-treprostinil | Bosentan or ambrisentan or sildenafil or tadalafil; | PVR, mPAP, CI, RAP, SvO2, NT-proBNP, 6MWD | Peripheral oedema, nasal congestion, flushing |
Hassoun, 2015 [10] | 24 | SSc-PAH | 59.9 | 36 weeks | II: 8 (35) III: 15 (65) | Ambrisentan-tadalafil | NA | PVR, mPAP, CI, RAP, NT-proBNP, 6MWD | Peripheral oedema, nasal congestion, dyspnoea, cough, headache, dizziness, fatigue, abdominal pain, nausea-vomiting, hypotension, diarrhoea |
Kemp, 2012 [11] | 23 | IPAH, HPAH, DPAH | 43 | 4±1 months | III: 16 (70) IV: 7 (30) | Epoprostenol-bosentan | Epoprostenol monotherapy | PVR, mPAP, CI, RAP, SvO2, 6MWD | Jaw pain, facial flushing, headache, gastrointestinal disturbance, leg pain, catheter infections, increase in liver enzymes |
Rinaldi, 2018 [12] | 19 | PAH | NR | NR | II–III: 100 | Ambrisentan-tadalafil | Bosentan or sildenafil monotherapy or other ERAs or PDE5i monotherapy or bosentan-sildenafil or macitentan-sildenafil | PVR, mPAP, CI, RAP, SvO2, 6MWD | |
Sitbon, 2014 [13] | 19 | IPAH, HPAH, DPAH | 39.4 | 4 months | III: 8 (42) IV: 11 (58) | Bosentan-sildenafil-epoprostenol | NA | PVR, mPAP, CI, RAP, SvO2, 6MWD | Jaw pain, headache, diarrhoea, flushing, increase in liver enzymes |
Sitbon, 2016 [14] | 97 | PAH | 54.1 | 4.1 (3.5–4.9) months | II: 15 (15) III: 70 (72) IV: 12 (12) | Bosentan-sildenafil or bosentan-tadalafil or ambrisentan-sildenafil or ambrisentan-tadalafil | NA | PVR, mPAP, CI, RAP, SvO2, BNP, 6MWD | Peripheral oedema, increase in liver enzymes, blurred vision |
Sitbon, 2020 [15] | 46 | PAH | 57.4 | 16 weeks | II: 10 (21.7) III: 36 (78.3) | Macitentan-tadalafil | NA | PVR, mPAP, CI, RAP, SvO2, NT-proBNP, 6MWD | Peripheral oedema, headache, diarrhoea, dyspnoea, anaemia, asthenia, fatigue, increase in liver enzymes |
Sulica, 2019 [16] | 15 | PAH | 55.8 | 13.7±3.6 months | III: 93 IV: 7 | Macitentan-riociguat | NA | PVR, mPAP, CI, RAP, SvO2, BNP, 6MWD | Peripheral oedema, nasal congestion, headache, hypotension |
van de Veerdonk, 2017 [17] | 80 | IPAH, HPAH, DPAH | 49 | 12 months | II: 24 (30) III: 56 (70) | Bosentan-sildenafil or bosentan-tadalafil or ambrisentan-sildenafil or ambrisentan-tadalafil | Bosentan or ambrisentan or macitentan or sitaxentanor or sildenafil or tadalafil | PVR, mPAP, CI, RAP, SvO2, NT-proBNP, 6MWD | Increase in liver enzymes |
Zhang, 2014 [18] | 68 | CHD-PAH | NR | 6 months | NR | Upfront iloprost-tadalafil | Sequential iloprost-tadalafil | PVR, SvO2, 6MWD |
Data are presented as n, mean±sd, median (interquartile range) or n (%). PAH: pulmonary arterial hypertension; WHO: World Health Organization; IPAH: idiopathic pulmonary arterial hypertension; ERA: endothelin receptor antagonist; PDE5i: phosphodiesterase type 5 inhibitor; PVR: pulmonary vascular resistance; mPAP: mean pulmonary arterial pressure; CI: cardiac index; RAP: right atrial pressure; 6MWD: 6-min walk distance; NR: not reported; CTD: connective tissue disorder; CHD: congenital heart disease; NA: not applicable; SvO2: mixed venous oxygen saturation; NT-proBNP: N-terminal pro-brain natriuretic peptide; SSc: systemic sclerosis; HPAH: heritable pulmonary arterial hypertension; DPAH: drug-induced pulmonary arterial hypertension. #: in this study, group 1 was treated with treprostinil-tadalafil or treprostinil-ambrisentan or treprostinil-bosentan or epoprostenol-tadalafil or epoprostenol-bosentan or iloprost-ambrisentan; group 2 was treated with ambrisentan-tadalafil or ambrisentan-sildenafil or bosentan-tadalafil or bosentan-sildenafil or macitentan-tadalafil or macitentan-sildenafil; group 3 was treated with bosentan or ambrisentan or sildenafil or tadalafil; group 4 was treated with treprostinil or epoprostenol.