Figures
- FIGURE 1
Forest plot of the effects of initial combination therapy on the pulmonary vascular resistance (PVR) expressed as percentage difference compared to baseline. TE: treatment effect; seTE: standard error of treatment effect; MD: mean difference.
- FIGURE 2
Effects of upfront combination therapy on haemodynamic outcomes in the single-arm meta-analysis. MD: mean difference; PVR: pulmonary vascular resistance; mPAP: mean pulmonary arterial pressure; RAP: right atrial pressure; SvO2: mixed venous oxygen saturation.
- FIGURE 3
Bubble plot for the effect of participants’ mean age on the pulmonary vascular resistance (PVR) outcome.
Tables
- TABLE 1
Baseline characteristics of included studies
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+PDE5iGroup 3: ERAs or PDE5i
Group 4: prostanoidsPVR, 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: 7Macitentan-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.
Supplementary Material
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Supplementary material 00313-2022.SUPPLEMENT
