Key randomised controlled trials and sub-group analyses in systemic sclerosis (SSc)-pulmonary arterial hypertension (PAH)
| Study [ref.] | Drug | Study length | CTD patients n | CTD type | Outcome in overall/comparator study | Outcomes in CTD sub-group |
| Nitric oxide pathway | ||||||
| SUPER-1 [47, 48] | Sildenafil 20 mg, 40 mg, 80 mg three times daily | 12 weeks | 84 | 45% SSc, 23% SLE, 32% other | Primary: mean placebo-adjusted change in 6MWD +45 m* (20 mg), +46 m* (40 mg), +50 m* (80 mg) Secondary: improvement in WHO FC in 7% (placebo), 28%* (20 mg), 36%* (40 mg), 42%* (80 mg) mPAP: −2.1 mmHg* (20 mg), −2.6 mmHg* (40 mg), −4.7 mmHg* (80 mg) | Primary: 6MWD −13 m (placebo), +42 m* (20 mg), +36 m ns (40 mg), +15 m ns (80 mg) Secondary: improvement in WHO FC in 5% (placebo), 29%* (20 mg), 40%* (40 mg), 42%* (80 mg) mPAP: −4.6 mmHg* (20 mg), −2.8 mmHg ns (40 mg), −3.2 mmHg ns (80 mg) |
| PHIRST-1 [49, 50] | Tadalafil 2.5mg–40 mg once daily 53% background Bosentan | 16 weeks | 56 | Unknown | Primary: mean placebo-adjusted change in 6MWD +27 m* (20 mg), +33 m* (40 mg) Secondary: no overall significant effect on WHO FC Time to clinical worsening improved in 40 mg dose* | Primary: exact distances not specified but comparable to IPAH Secondary: higher proportion worsened and lower proportion improved WHO FC in CTD-PAH cf IPAH Higher rate of clinical worsening in 40 mg dose (11% versus 4% IPAH) |
| PATENT-1 [51, 52] | Riociguat up to 2.5 mg three times daily 44% background ERA 6% background prostanoid | 12 weeks | 111 | 59% SSc, 16% SLE, 25% other | Primary: treatment arm 6MWD +30 m versus placebo −6 m (mean placebo-adjusted change +36 m*) Secondary: placebo: improvement in WHO FC in 14% and worsening in 14%; treatment: improvement in WHO FC in 21% and worsening in 4%* PVR: −9 dyn·s·cm−5 (placebo) versus −223 dyn·s·cm−5 (treatment)* NT-proBNP: +232 pg·mL−1 (placebo) versus −198 pg·mL−1 (treatment)* | Primary: SSc treatment arm 6MWD +4 m versus placebo −37 m* Secondary: SSc placebo: improvement in WHO FC in 13% and worsening in 27%; treatment: improvement in WHO FC in 16% and worsening in 2%* PVR: −79 dyn·s·cm−5 (placebo) versus −132 dyn·s·cm−5 (treatment) NT-proBNP: +142 pg·mL−1 (placebo) versus +98 pg·mL−1 (treatment)* |
| ERA-1 | ||||||
| BREATHE-1 [53] | Bosentan 125–250 mg twice daily | 16 weeks | 63 | 75% SSc, 25% SLE | IPAH treatment arm 6MWD +46 m versus placebo −5 m* | SSc treatment arm 6MWD +3 m versus placebo −40 m |
| AMBITION [54, 55] | Ambrisentan 10 mg and/or Tadalafil 40 mg once daily | Mean 74 weeks | 187 | 63% SSc, 12% MCTD, 9% SLE | 50% risk reduction of combined morbidity/mortality end-point* | 56% risk reduction of combined morbidity/mortality end-point* |
| SERAPHIN [56] | Macitentan 10 mg once daily 64% on background PAH therapy | Mean 115 weeks | 224 | 63% SSc, 12% MCTD, 9% SLE | 50% risk reduction of combined morbidity/mortality end-point* | 56% risk reduction of combined morbidity/mortality end-point* |
| Prostanoid | ||||||
| [57, 58] | Intravenous epoprostenol | 12 weeks | 111 | 100% SSc | IPAH study treatment arm +47 m versus conventional therapy −66 m* Secondary: mPAP mean placebo-adjusted difference −6.7 mmHg* PVR mean placebo-adjusted difference −4.9 WU* | Primary: treatment arm 6MWD +46 m versus conventional therapy −48 m* Secondary: mPAP mean placebo-adjusted difference −6 mmHg* PVR mean placebo-adjusted difference −5.5 WU* |
| [59, 60] | Subcutaneous treprostinil Background therapy unclear | 12 weeks | 90 | 50% SSc, 28% SLE, 19% MCTD | Primary: treatment arm 6MWD median +10 m versus placebo +0 m* Secondary: mPAP −2.3 mmHg*, PVRi −3.5 WU·m−2* | Primary: treatment arm 6MWD +24 m versus placebo +3 m Secondary: mPAP −3 mmHg, PVRi −4 WU·m−2* |
| GRIPHON [61, 62] | Selexipag 200–1600 µg twice daily 80% on background PAH therapy | Mean 70 weeks | 334 | 51% SSc, 25% SLE, 25% MCTD/other | 40% risk reduction of combined morbidity/mortality end-point* | 41% risk reduction of combined morbidity/mortality end-point* |
CTD: connective tissue disease; ERA-1: endothelin receptor antagonist-1; SLE: systemic lupus erythematosus; 6MWD: 6-min walk distance; WHO FC: World Health Organization functional class; mPAP: mean pulmonary arterial pressure; ns: nonsignificant; IPAH: idiopathic pulmonary arterial hypertension; PVR: pulmonary vascular resistance; NT-proBNP: N-terminal pro-brain natriuretic peptide; MCTD: mixed connective tissue disease; PVRi: PVR index; WU: Wood Units. *: p<0.05.