Combination trials with endothelin receptor antagonists(ERAs) in pulmonary arterial hypertension
| First-line drug | Added therapy (type) | Current, complete and published studies# | Subjects n | Duration | Primary end-point(s) | Significantly improved? | Other end-points |
| Bosentan | Inhaled iloprost (prostanoid) | [75] | 67 | 12 weeks | 6MWD, BDI, NYHA FC, TCW | No, yes, yes, yes | Improved HD (P̄pa, PVR)No change HD (others) |
| Bosentan | Inhaled iloprost (prostanoid) | Terminated [55] | 40 | 12 weeks | 6MWD | No | |
| Epoprostenol | Bosentan (ERA) | [74] | 33 | 16 weeks | TPR | No | No change 6MWD, NYHA FC, HD (CI, PVR, P̄pa, P̄ra) |
| Bosentan | Tadalafil (PDE5i) | [77] | 216 | 16 weeks | 6MWD | No (40 mg combination) | Improved WHO FC (40 mg combination) |
| Bosentan or sildenafil | Iloprost power 15 disc | Recruiting PROWESS 15 (NCT00709956) | ∼63 | Single dose | 6MWD | NA | BDI |
| Bosentan or sildenafil | Inhaled treprostinil (prostanoid) | Ongoing TRIUMPH (NCT00147199) | ∼235 | 12 weeks | 6MWD | NA | NYHA FC, BDI, QOL, TCW |
| Approved ERA, PDE5I or both | Oral treprostinil (prostanoid) | Completed FREEDOM-C (NCT00325442) | ∼300 | 16 weeks | 6MWD | NA | BDI, TCW, dyspnoea–fatigue index, WHO FC |
| Approved ERA, PDE5I or both | Oral treprostinil (prostanoid) | Terminated FREEDOM-DR (NCT00760916) | ∼170 | 12 weeks | 6MWD | NA | BDI, TCW, dyspnoea–fatigue index; WHO FC; trough 6MWD and BDI, NT-proBNP, HD |
| Approved ERA, PDE5I or both | Oral treprostinil (prostanoid) | Recruiting FREEDOM-C2 (NCT00887978) | NR | 16 weeks | 6MWD | NA | BDI, TCW, dyspnoea–fatigue index, WHO FC, NT-proBNP, QOL, biomarkers |
| Approved PAH therapy | Imatinib (tyrosine kinase inhibitor) | Ongoing (NCT00477269) | ∼60 | 6 months | Safety | NA | WHO FC, BDI, HD, TCW, biomarkers |
| ERA | Riociguat (cGMP activator) | Recruiting (NCT00810693) | ∼462 | 12 weeks | 6MWD | NA | PVR, NT-proBNP, WHO FC, TCW, BDI, EQ-5D |
| Approved PDE5I | Ambrisentan (ERA) | Recruiting ATHENA-1 (NCT00617305) | ∼40 | 24 weeks | PVR (also P̄pa, P̄ra, CO as supportive) | NA | 6MWD, BDI, TCW, WHO FC, NT-proBNP, CAMPHOR QOL, survival |
| Bosentan | Sildenafil (PDE5I) | Recruiting (NCT00323297) | ∼106 | 12 weeks | 6MWD | NA | TCW, BDI, FC |
| Bosentan | Sildenafil (PDE5I) | COMPASS-1 | ∼45 | Single dose | PVR | NA | TPR, NT-proBNP, acute vasoreactivity |
| Sildenafil | Bosentan (ERA) | Recruiting COMPASS-2 (NCT00303459) | ∼250 | 16 weeks | Time to first morbidity/mortality event | NA | WHO FC, BDI, EQ-5D, 6MWD, TCW/death, patient global self-assessment |
| Bosentan | Sildenafil (PDE5I) | Recruiting COMPASS-3 (NCT00433329) | ∼100 | 28 weeks | 6MWD (380 m) | NA | MRI parameters |
| First-line combination | |||||||
| Sitaxentan + sildenafil (PDE5i) | Recruiting (NCT00796666) | ∼180 | 12, 24 and 48-week assessments | TCW | NA | 6MWD, WHO FC, SF-36 |
PDE5I: phosphodiesterase type 5 inhibitor; cGMP: cyclic guanosine monophosphate; 6MWD: 6-min walk distance; BDI: Borg dyspnoea index; NYHA: New York Heart Association; FC: functional class; TCW: time to clinical worsening; TPR: total pulmonary resistance; PVR: pulmonary vascular resistance; P̄pa: mean pulmonary arterial pressure; P̄ra: mean right atrial pressure; CO: cardiac output; NA: not applicable; HD: haemodynamics; CI: cardiac index; WHO: World Health Organization; QOL: quality of life; NT-proBNP: N-terminal pro-brain natriuretic peptide; EQ-5D: EuroQol 5 Dimensions; CAMPHOR: Cambridge Pulmonary Hypertension Outcome Review; MRI: magnetic resonance imaging; SF-36: Short Form-36. #: the registered National Clinical Trial number is given in parentheses.